This invention relates to methods, pharmaceutical compositions and kits comprising an aldose reductase inhibitor (ARI), a prodrug thereof or a pharmaceutically acceptable salt of said ARI or said prodrug and a selective cyclooxygenase-2 (COX-2) inhibitor, a prodrug thereof or a pharmaceutically acceptable salts of said selective COX-2 inhibitor or said prodrug. This invention further relates to methods of using such pharmaceutical compositions for the treatment of diabetic complications such as diabetic neuropathy, diabetic nephropathy, diabetic retinopathy, myocardia infarction, cataracts and diabetic cardiomyopathy.
Aldose reductase inhibitors function by inhibiting the activity of the enzyme aldose reductase, which is primarily responsible for regulating the reduction of aldoses, such as glucose and galactose, to the corresponding polyols, such as sorbitol and galactitol, in humans and other animals. In this way, unwanted accumulations of galactitol in the lens of galactosemic subjects and of sorbitol in the lens, peripheral nervous cord and kidneys of various diabetic subjects are prevented or reduced. Accordingly, aldose reductase inhibitors are of therapeutic value for controlling certain diabetic complications, e.g., diabetic neuropathy, diabetic nephropathy, diabetic cardiomyopathy, myocardial infarction, cataracts and diabetic retinopathy.
Two forms of cylcooxygenase (COX) known to exist: COX-1 and COX-2, the former being a constitutive form and the latter being an inducible form. COX-1 exists in the stomach, intestines, kidneys and platelets while COX-2 is expressed during inflammation. Both COX enzyme isoforms metabolize arachidonic by a similar mechanism, but each have different substrate specificities. Selective COX-2 inhibitors are advantageous in the treatment of pain and inflammation while avoiding such side effects as gastric and renal toxicity.
This invention is directed to pharmaceutical compositions comprising an aldose reductase inhibitor (ARI), a prodrug thereof or a pharmaceutically acceptable salt of said ARI or of said prodrug;
(a) a selective cyclooxygenase-2 (COX-2) inhibitor of formula I, 
xe2x80x83a prodrug thereof or a pharmaceutically acceptable salt thereof or of said prodrug,
xe2x80x83wherein the variables of the compound of formula I are defined as follows:
R1 is hydrogen or (C1-C4)alkyl; R2 is C(xe2x95x90Lxe2x80x2)R3 or SO2R4; Y is a direct bond or (C1-C4)alkylene; L and Lxe2x80x2 are independently oxygen or sulfur;
Q is selected from the following:
(Q-a) (C1-C6)alkyl;
(Q-b) halo-substituted (C1-C4)alkyl;
(Q-c) (C3-C7)cycloalkyl optionally substituted with one or two substituents independently selected from (C1-C4)alkyl, halo-substituted (C1-C4)alkyl, (C1-C4)alkoxy, hydroxy and halo;
(Q-d) phenyl or naphthyl, the phenyl and naphthyl being optionally substituted with one, two or three substituents independently selected from halo, (C1-C4)alkyl, halo-substituted (C1-C4)alkyl, hydroxy, (C1-C4)alkoxy, nitro, halo-substituted (C1-C4)alkoxy, S(O)mR5, SO2NH2, SO2N((C1-C4)alkyl)2, amino, (C1-C4)alkylamino, di-((C1-C4)alkyl)amino, NR1 C(O)R5, CN, (C1-C4)alkyl-OH and (C1-C4)alkyl-OR5;
(Q-e) a 5-membered monocyclic aromatic group containing one heteroatom selected from O, S and N and optionally containing one, two or three nitrogen atom(s) in addition to said heteroatom, and said monocyclic aromatic group being optionally substituted with one, two or three substituents independently selected from halo, (C1-C4)alkyl, halo-substituted (C1-C4)alkyl, hydroxy, (C1-C4)alkoxy, halo-substituted (C1-C4)alkoxy, amino, (C1-C4) alkylamino, di-((C1-C4)alkyl)amino, (C1-C4)alkyl-OH and (C1-C4)alkyl-OR5; and
(Q-f) a 6-membered monocyclic aromatic group containing one nitrogen atom and optionally containing one, two or three additional nitrogen atom(s), and said monocyclic aromatic group being optionally substituted with one, two or three substituents independently selected from halo, (C1-C4)alkyl, halo-substituted (C1-C4)alkyl, hydroxy, (C1-C4)alkoxy, halo-substituted (C1-C4)alkoxy, amino, (C1-C4)alkylamino, di-((C1-C4)alkyl)amino, (C1-C4)alkyl-OH and (C1-C4)alkyl-OR5;
R3 is xe2x80x94OR6, xe2x80x94NR7R8, N(OR1)R7 or a group of formula: 
xe2x80x83Z is a direct bond, oxygen, sulfur or NR5;
R4 is (C1-C6)alkyl, halo-substituted (C1-C4)alkyl, (C1-C4)alkyl-OH, xe2x80x94NR7R8, phenyl or naphthyl, the phenyl and naphthyl being optionally substituted with one, two or three substituents independently selected from halo, (C1-C4)alkyl, halo-substitutued (C1-C4)alkyl, hydroxy, (C1-C4)alkoxy and halo-substitutued (C1-C4)alkoxy;
R5 is (C1-C4)alkyl or halo-substituted (C1-C4)alkyl;
R6 is (C1-C4)alkyl, (C3-C7)cycloalkyl, (C1-C4)alkyl-(C3-C7)cycloalkyl, halo-substitutued (C1-C4)alkyl, (C1-C4)alkyl-phenyl or phenyl, the phenyl moiety being optionally substituted with one, or two substituents independently selected from halo, (C1-C4)alkyl, halo-substitutued (C1-C4)alkyl, hydroxy, (C1-C4)alkoxy, (C1-C4)alkylthio, amino, di-((C1-C4)alkyl)amino and nitro;
R7 and R8 are independently selected from I hydrogen, (ii) (C1-C6)alkyl optionally substituted with a substituent independently selected from halo, hydroxy, (C1-C4)alkoxy, amino, (C1-C4)alkylamino and di-((C1-C4)alkyl)amino, (iii) (C3-C7)cycloalkyl optionally substituted with a substituent independently selected from hydroxy, (C1-C4)alkyl and (C1-C4)alkoxy, (iv) (C1-C4)alkyl-(C3-C7)cycloalkyl optionally substituted with a substituent independently selected from hydroxy, (C1-C4)alkyl and (C1-C4)alkoxy, and (v) (C1-C4)alkyl-phenyl or phenyl, the phenyl moiety being optionally substituted with one or two substituents independently selected from halo, (C1-C4)alkyl, halo-substitutued (C1-C4)alkyl, hydroxy, (C1-C4)alkoxy, (C1-C4)alkylthio, nitro, amino, di-((C1-C4)alkyl)amino and CN;
X is independently selected from halo, (C1-C4)alkyl, halo-substitutued (C1-C4)alkyl, hydroxy, (C1-C4)alkoxy, halo-substitutued (C1-C4)alkoxy, (C1-C4)alkylthio, nitro, amino, di-((C1-C4)alkyl)amino and CN;
m is 0, 1 or 2; n is 0, 1, 2 or 3; and r is 1, 2 or 3; or
(b) a selective COX-2 inhibitor of formula XX, 
xe2x80x83a prodrug thereof or a pharmaceutically acceptable salt thereof or of said prodrug,
xe2x80x83wherein the variables of the compound of formula XX are defined as follows:
A is a partially unsaturated or unsaturated five membered heterocyclic, or a partially unsaturated or unsaturated five membered carbocyclic, wherein the 4-(sulfonyl)phenyl and the 4-substituted phenyl in the formula XX are attached to ring atoms of Ring A adjacent to each other;
R1 is aryl or heteroaryl, and the aryl or heteroaryl being optionally substituted by one to four substituents selected from halo, (C1-C4)alkyl, halo-substituted (C1-C4)alkyl, (C1-C4)alkoxy, (C1-C4)alkyl carbonyl, hydroxy, nitro, cyano and amino, with the proviso that when A is pyrazole, R1 is heteroaryl;
R2 is (C1-C4)alkyl, halo-substituted (C1-C4)alkyl, (C1-C4)alkylamino, (C1-C4)dialkylamino or amino;
R3, R4 and R5 are independently hydrogen, halo, (C1-C4)alkyl, halo-substituted (C1-C4)alkyl, (C2-C5)alkenyl, (C2-C5)alkynyl, (C1-C4)alkoxy, hydroxy-(C1-C4)alkyl, (C1-C4)alkoxy (C1-C4)alkyl, (C1-C4)alkanoyl, cyano, nitro, cyano (C1-C4)alkyl, carboxy, (C1-C4)alkoxycarbonyl, aminocarbonyl, Nxe2x80x94(C1-C4)alkylaminocarbonyl, N,N-di-(C1-C4)alkylaminocarbonyl, N-arylaminocarbonyl, N,N-diarylaminocarbonyl, Nxe2x80x94(C1-C4)alkyl-N-arylaminocarbonyl, aryl, aryloxy, aryloxy-(C1-C4)alkyl, heteroaryl, heteroaryloxy, heteroaryloxy-(C1-C4)alkyl, morpholino-carbonyl, (C1-C4)alkoxyaminocarbonyl or (C1-C4)alkyl-carbonylamino; or two of R3, R4 and R5 are taken together with atoms to which they are attached and form a 4-7 membered ring;
R6 and R7 are independently hydrogen, halo, (C1-C4)alkyl, halo-substituted (C1-C4)alkyl, (C1-C4)alkoxy, (C1-C4)alkylthio, (C1-C4)alkylamino, N,N-di(C1-C4)alkylamino, hydroxyl-(C1-C4)alkyl, (C1-C4)alkoxy-(C1-C4)alkyl, (C1-C4)alkyl -(C1-C4)alkoxy, (C1-C4)alkylamino-(C1-C4)alkyl, hydroxy, amino-(C1-C4)alkyl and N,N-di(C1-C4)alkylamino -(C1-C4)alkyl; and
m and n are independently 1, 2, 3 or 4,
with the proviso that when A contains an oxygen or sulfur heteroatom, one of R3, R4 or R5 is absent; or
(c) a selective COX-2 inhibitor of formula XXX, 
xe2x80x83a prodrug thereof or a pharmaceutically acceptable salt thereof or of said prodrug,
xe2x80x83wherein variables of the compound of formula XXX are defined as follows:
Ar is heteroaryl selected from a 5-membered monocyclic aromatic ring having one hetero atom selected from O, S and N and optionally containing one to three N atom(s) in addition to said hetero atom, or a 6-membered monocyclic aromatic ring having one N atom and optionally containing one to four N atom(s) in addition to said N atom; and said heteroaryl being connected to the nitrogen atom on the benzimidazole through a carbon atom on the heteroaryl ring;
X1 is independently selected from halo, (C1-C4)alkyl, hydroxy, (C1-C4)alkoxy, halo-substituted (C1-C4)alkyl, hydroxy-substituted (C1-C4)alkyl, ((C1-C4)alkoxy)(C1-C4)alkyl, halo-substituted (C1-C4)alkoxy, amino, Nxe2x80x94((C1-C4)alkyl)amino, N,N-di((C1-C4)alkyl)amino, [Nxe2x80x94((C1-C4)alkyl)amino](C1-C4)alkyl, [N,N-di((C1-C4)alkyl)amino](C1-C4)alkyl, Nxe2x80x94((C1-C4)alkanoyl)amino, Nxe2x80x94((C1-C4)alkyl)-Nxe2x80x94((C1-C4)alkanoyl)amino, Nxe2x80x94[((C1-C4)alkyl)sulfonyl]amino, N-[(halo-substituted (C1-C4)alkyl)sulfonyl]amino, (C1-C4)alkanoyl, carboxy, ((C1-C4)alkoxy)carbonyl,carbamoyl, (Nxe2x80x94((C1-C4)alkyl)amino]carbonyl, [N,N-di((C1-C4)alkyl)amino]carbonyl, cyano, nitro, mercapto, ((C1-C4)alkyl)thio, ((C1-C4)alkyl)sulfinyl, ((C1-C4)alkyl)sulfonyl, aminosulfonyl, [Nxe2x80x94((C1-C4)alkyl)amino]sulfonyl and [N,N-di((C1-C4)alkyl)amino]sulfonyl;
X2 is independently selected from halo, (C1-C4)alkyl, hydroxy, (C1-C4)alkoxy, halo-substituted (C1-C4)alkyl, hydroxy-substituted (C1-C4)alkyl, ((C1-C4)alkoxy)(C1-C4)alkyl, halo-substituted (C1-C4)alkoxy, amino, Nxe2x80x94((C1-C4)alkyl)amino, N,N-di((C1-C4)alkyl)amino, [Nxe2x80x94((C1-C4)alkyl)amino](C1-C4)alkyl, [N,N-di((C1-C4)alkyl)amino](C1-C4)alkyl, Nxe2x80x94((C1-C4)alkanoyl)amino, Nxe2x80x94((C1-C4)alkyl)-Nxe2x80x94((C1-C4)alkanoyl)amino, Nxe2x80x94[((C1-C4)alkyl)sulfonyl]amino, N-[(halo-substituted (C1-C4)alkyl)sulfonyl]amino, (C1-C4)alkanoyl, carboxy, ((C1-C4)alkoxy)carbonyl, carbamoyl, [Nxe2x80x94((C1-C4)alkyl)amino]carbonyl, [N,N-di((C1-C4)alkyl)amino]carbonyl, N-carbamoylamino, cyano, nitro, mercapto, ((C1-C4)alkyl)thio, ((C1-C4)alkyl)sulfinyl, ((C1-C4)alkyl)sulfonyl, aminosulfonyl, [Nxe2x80x94((C1-C4)alkyl)amino]sulfonyl and [N,N-di((C1-C4)alkyl)amino]sulfonyl;
R1 is selected from
hydrogen;
straight or branched (C1-C4)alkyl optionally substituted with up to three substituents wherein said substituents are independently selected from halo, hydroxy, (C1-C4)alkoxy, amino, Nxe2x80x94((C1-C4)alkyl)amino and N,N-di((C1-C4)alkyl)amino;
(C3-C8)cycloalkyl optionally substituted with up to three substituents wherein said substituents are independently selected from halo, (C1-C4)alkyl, hydroxy, (C1-C4)alkoxy, amino, Nxe2x80x94((C1-C4)alkyl)amino and N,N-di((C1-C4)alkyl)amino;
(C4-C8) cycloalkenyl optionally substituted with up to three substituents wherein said substituents are independently selected from halo, (C1-C4)alkyl, hydroxy, (C1-C4)alkoxy, amino, Nxe2x80x94((C1-C4)alkyl)amino and N,N-di((C1-C4)alkyl)amino;
phenyl optionally substituted with up to three substituents wherein said substituents are independently selected from halo, (C1-C4)alkyl, hydroxy, (C1-C4) alkoxy, halo-substituted (C1-C4)alkyl, hydroxy-substituted (C1-C4)alkyl, ((C1-C4)alkoxy)(C1-C4)alkyl, halo-substituted (C1-C4)alkoxy, amino, Nxe2x80x94((C1-C4)alkyl)amino, N,N-di((C1-C4)alkyl)amino, [Nxe2x80x94((C1-C4)alkyl)amino](C1-C4)alkyl, [N,N-di((C1-C4)alkyl)amino](C1-C4)alkyl, Nxe2x80x94((C1-C4)alkanoyl)amino, Nxe2x80x94[((C1-C4)alkyl)((C1-C4)alkanoyl)]amino, Nxe2x80x94[((C1-C4)alkyl)sulfonyl]amino, N-[(halo-substituted (C1-C4)alkyl)sulfonyl]amino, (C1-C4)alkanoyl, carboxy, ((C1-C4)alkoxy)carbonyl, carbamoyl, [Nxe2x80x94((C1-C4)alkyl)amino]carbonyl, [N,N-di((C1-C4)alkyl)amino]carbonyl, cyano, nitro, mercapto, ((C1-C4)alkyl)thio, ((C1-C4)alkyl)sulfinyl, ((C1-C4)alkyl)sulfonyl, aminosulfonyl, [Nxe2x80x94((C1-C4)alkyl)amino]sulfonyl and [N,N-di((C1-C4)alkyl)amino]sulfonyl; and
heteroaryl selected from
a 5-membered monocyclic aromatic ring having one hetero atom selected from O, S and N and optionally containing one to three N atom(s) in addition to said hetero atom; or
a 6-membered monocyclic aromatic ring having one N atom and optionally containing one to four N atom(s) in addition to said N atom; and
said heteroaryl is optionally substituted with up to three substituents selected from X1;
R2 and R3 are independently selected from
hydrogen;
halo;
(C1-C4)alkyl;
phenyl optionally substituted with up to three substituents wherein said substituents are independently selected from halo, (C1-C4)alkyl, hydroxy, (C1-C4)alkoxy, amino, Nxe2x80x94((C1-C4)alkyl)amino and N,N-di((C1-C4)alkyl)amino;
m is 0, 1, 2, 3, 4 or 5; and
n is 0, 1, 2, 3 or 4; or
(d) a selective COX-2 inhibitor of formula XL, 
xe2x80x83a prodrug thereof or a pharmaceutically acceptable salt thereof or of said prodrug
xe2x80x83wherein the variables of the compound of formula XL are defined as follows:
Z is OH, (C1-C6)alkoxy, xe2x80x94NR2R3 or a group of formula II or formula III: 
xe2x80x83wherein r is 1,2, 3 or 4, Y is a direct bond, O, S or NR4, and W is OH or xe2x80x94NR2R3;
Q is selected from the following:
(A) phenyl optionally substituted with one, two or three substituents independently selected from
(i) halo, (C1-C4)alkyl, halo-substituted (C1-C4)alkyl, OH, (C1-C4)alkoxy, halo-substituted (C1-C4)alkoxy, (C1-C4)alkylthio, NO2, NH2, di-((C1-C4)alkyl)amino, (C1-C4)alkylamino, CN, HOxe2x80x94(C1-C4)alkyl, (C1-C4)alkoxy-(C1-C4)alkyl, (C1-C4)alkylsulfonyl, aminosulfonyl, xe2x80x94NH2S(O)2NR2R3, acetyl, xe2x80x94COOH, xe2x80x94C(O)Oxe2x80x94(C1-C4)alkyl, (C1-C4)alkylsulfonylamino and (C3-C7)cycloalkyl;
(ii) aryl or xe2x80x94Oxe2x80x94(CH2)n-aryl, wherein either aryl moiety is optionally substituted with one, two or three substituents independently selected from halo, (C1-C4)alkyl, halo-substituted (C1-C4)alkyl, OH, (C1-C4)alkoxy, halo-substituted (C1-C4)alkoxy, (C1-C4)alkylthio, NO2, NH2, di-((C1-C4)alkyl)amino, (C1-C4)alkylamino and CN;
(iii) 5-membered monocyclic aromatic group optionally substituted with one, two or three substituents independently selected from halo, (C1-C4)alkyl, halo-substituted (C1-C4)alkyl, OH, (C1-C4)alkoxy, halo-substituted (C1-C4)alkoxy, (C1-C4)alkylthio, NO2, NH2, di-((C1-C4)alkyl)amino, (C1-C4)alkylamino and CN;
(iv) 6-membered monocyclic aromatic group optionally substituted with one, two or three substituents independently selected from halo, (C1-C4)alkyl, halo-substituted (C1-C4)alkyl, OH, (C1-C4)alkoxy, halo-substituted (C1-C4)alkoxy, (C1-C4)alkylthio, NO2, NH2, di-((C1-C4)alkyl)amino, (C1-C4)alkylamino and CN;
(B) a 6-membered monocyclic aromatic group containing one, two, three or four nitrogen atom(s), and said monocyclic aromatic group being optionally substituted with one, two or three substituents independently selected from the above group i, ii, iii and iv;
(C) a 5-membered monocyclic aromatic group containing one heteroatom selected from O, S and N and optionally containing one, two or three nitrogen atom(s) in addition to said heteroatom, and said monocyclic aromatic group being optionally substituted with one, two or three substituents independently selected from the above group i, ii, iii and iv;
(D) (C3-C7)cycloalkyl optionally substituted with one or two substituents independently selected from OH, (C1-C4)alkyl, halo and halo-substituted (C1-C4)alkyl; and
(E) a benzo-fused heterocycle optionally substituted with one, two or three substituents independently selected from the group (a-1);
R1 is hydrogen, (C1-C4)alkyl or halo;
R2 and R3 are independently H, OH, (C1-C4)alkoxy, (C1-C4)alkyl or (C1-C4)alkyl substituted with halo, OH, (C1-C4)alkoxy, NH2 or CN;
R4 is hydrogen or (C1-C4)alkyl;
X is independently selected from halo, (C1-C4)alkyl, halo-substituted (C1-C4)alkyl, OH, (C1-C4)alkoxy, halo-substituted (C1-C4)alkoxy, (C1-C4)alkylthio, NO2, NH2, di-((C1-C4)alkyl)amino, (C1-C4)alkylamino, CN, HOxe2x80x94(C1-C4)alkyl, (C1-C4) alkoxy-(C1-C4)alkyl, (C1-C4)alkylsulfonyl, aminosulfonyl, xe2x80x94NH2S(O)2NR2NR3, acetyl, xe2x80x94COOH, xe2x80x94C(O)Oxe2x80x94(C1-C4)alkyl, (C1-C4)alkylsulfonylamino and (C3-C7)cycloalkyl; and
n is 0, 1, 2, 3 or 4; or
(e) a selective COX-2 inhibitor of formula L, 
xe2x80x83a prodrug thereof or a pharmaceutically acceptable salt thereof or of said prodrug
xe2x80x83wherein the variables of the compound of formula L are defined as follows:
Ar is phenyl, (C3-C8)cycloalkyl, (C4-C8)cycloalkenyl or heteroaryl which is connected to Y through a carbon atom, the heteroaryl being selected from pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, furyl, thienyl, oxazolyl, thiazolyl, isooxazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxadiazolyl, triazolyl and tetrazolyl;
X1 is H, halo, (C1-C4)alkyl, hydroxy, (C1-C4)alkoxy, halo-substituted (C1-C4)alkyl, hydroxy-substituted (C1-C4)alkyl, (C1-C4)alkoxy(C1-C4)alkyl, amino, (C1-C4)alkylamino, di(C1-C4)alkylamino, amino (C1-C4)alkyl, (C1-C4)alkylamino(C1-C4)alkyl, di(C1-C4)alkylamino(C1-C4)alkyl, (C1-C4)alkanoylamino, di(C1-C4)alkanoylamino, (C1-C4)alkyl((C1-C4)alkanoyl)amino, (C1-C4)alkylsulfonylamino, (C1-C4)alkanoyl, carboxyl, (C1-C4)alkoxycarbonyl, aminocarbonyl, (C1-C4)alkylaminocarbonyl, di(C1-C4)alkylaminocarbonyl, cyano, nitro, mercapto, (C1-C4)alkylthio, (C1-C4)alkylsulfinyl, (C1-C4)alkylsufonyl, aminosufonyl, (C1-C4)alkylaminosufonyl or di(C1-C4)alkylaminosulfonyl;
X2 and X3 are independently (C1-C4)alkyl, halo, halo-substituted (C1-C4)alkyl, hydroxy, (C1-C4)alkoxy, mercapto, (C1-C4)alkylthio, (C1-C4)alkylsulfinyl, (C1-C4)alkylsulfonyl, (C1-C4)alkanoyl, carboxyl, (C1-C4)alkoxycarbonyl, aminocarbonyl, (C1-C4)alkylaminocarbonyl, di(C1-C4)alkylaminocarbonyl, cyano, nitro, amino, (C1-C4)alkylamino, di(C1-C4)alkylamino or (C1-C4)alkylsulfonylamino;
Y is xe2x80x94CR2xe2x95x90CR2xe2x80x94 or xe2x80x94Cxe2x89xa1Cxe2x80x94, wherein R1 and R2are independently H, methyl, ethyl or halo;
p is 0, 1, 2, 3 or4; and
m and n are independently 0, 1, 2 or 3,
with the proviso that when Ar is phenyl; and p, m and n are 0, Y is not xe2x80x94CHxe2x95x90CHxe2x80x94; and
when Ar is phenyl; p and m are 0; n is 1; and Y is xe2x80x94CHxe2x95x90CHxe2x80x94, X3 is not (C1-C4)alkoxy attached to the 2-position of Ar, nor amino, (C1-C4)alkylamino or di(C1-C4)alkylamino attached at the 4-position of Ar; or
(f) a selective COX-2 inhibitor of formula LX, 
xe2x80x83a prodrug thereof or a pharmaceutically acceptable salt thereof or of said prodrug
xe2x80x83wherein the variables of the compound of formula LX are defined as follows:
Xxe2x80x94Yxe2x80x94Zxe2x80x94 is selected from the group consisting of xe2x80x94C(O)xe2x80x94Oxe2x80x94CR5(R5)xe2x80x94 when side b is a double bond, and sides a and c are single bonds; and
R1 is selected from the group consisting of S(O)2CH3 and S(O)2NH2;
R2 is selected from the group consisting of (C1-C6)alkyl, (C3-C7)cycloalkyl, heteroaryl, benzoheteroaryl and mono- or di-substituted phenyl wherein the substituent is selected from the group consisting of hydrogen, halo, (C1-C6)alkoxy, (C1-C6)alkylthio, CN, CF3, (C1-C6)alkyl, N3, xe2x80x94CO2H, xe2x80x94CO2xe2x80x94(C1-C4)alkyl, xe2x80x94C(R5)(R6)xe2x80x94OH, xe2x80x94C(R5)(R6)xe2x80x94Oxe2x80x94(C1-C4)alkyl, and xe2x80x94(C1-C6)alkyl-CO2R5;
R5 and R6 are each independently selected from the group consisting of hydrogen and (C1-C6)alkyl,
or R5 and R6 together with the carbon to which they are attached from a saturated monocyclic carbon ring which is 3, 4, 5, 6 or 7 atoms;
and a pharmaceutically acceptable carrier, vehicle or diluent.
In the compositions, methods and kits of this invention, it is preferred that said selective COX-2 inhibitor is selected from the group consisting of:
ethyl(2-benzoyl-6-chloro-1H-indol-3-yl)acetate; (2-benzoyl-6-chloro-1H-indol-3-yl)acetic acid; (2-benzoyl-6-chloro-1H-indol-3-yl)acetic acid, sodium salt; [6-chloro-2-(2-methylbenzoyl)-1H-indol-3-yl]acetic acid; [6-chloro-2-(3-methylbenzoyl)-1H-indol-3-yl]acetic acid; [6-chloro-2-(4-methylbenzoyl)-1H-indol-3-yl]acetic acid; [6-chloro-2-(3-chlorobenzoyl)-1H-indol-3-yl]acetic acid; methyl [6-chloro-2-(4-chlorobenzoyl)-1H-indol-3-yl]acetate; [6-chloro-2-(4-chlorobenzoyl)-1H-indol-3-yl]acetic acid; [6-chloro-2-(3-fluorobenzoyl)-1H-indol-3-yl]acetic acid; [6-chloro-2-(4-fluorobenzoyl)-1H-indol-3-yl]acetic acid; [2-(3-bromobenzoyl)-6-chloro-1H-indol-3-yl]acetic acid; [2-(4-bromobenzoyl)-6-chloro-1H-indol-3-yl]acetic acid; [6-chloro-2-(3-trifluoromethylbenzoyl)-1H-indol-3-yl]acetic acid; [6-chloro-2-(4-trifluoromethylbenzoyl)-1H-indol-3-yl]acetic acid; [6-chloro-2-(3,4-dichlorobenzoyl)-1H-indol-3-yl]acetic acid; (2-benzoyl-4-chloro-1H-indol-3-yl)acetic acid; [5-chloro-2-(3-methylbenzoyl)-1H-indol-3-yl]acetic acid; [5-chloro-2-(4-chlorobenzoyl)-1H-indol-3-yl]acetic acid; [5-chloro-2-(3-chlorobenzoyl)-1H-indol-3-yl]acetic acid; [2-(4-chlorobenzoyl)-5-fluoro-1H-indol-3-yl]acetic acid; [2-(3-chlorobenzoyl)-5-fluoro-1H-indol-3-yl]acetic acid; [5-methoxy-2-(3-methylbenzoyl)-1H-indol-3-yl)acetic acid; (2-benzoyl-7-chloro-1H-indol-3-yl)acetic acid; (2-benzoyl-4,5-dichloro-1H-indol-3-yl)acetic acid; (2-benzoyl-4,6-dichloro-1H-indol-3-yl)acetic acid; (2-benzoyl-5,6-dichloro-1H-indol-3-yl)acetic acid; dl-2-(2-benzoyl-6-chloro-1H-indol-3-yl)propanoic acid; less polar antipode, 2-(2-benzoyl-6-chloro-1H-indol-3-yl)propanoic acid; more polar antipode, 2-(2-benzoyl-6-chloro-1H-indol-3-yl)propanoic acid; [6-chloro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; [6-chloro2-(5-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; methyl[6-chloro-2-(4-chloropyridine-2-carbonyl)-1H-indol-3-yl]acetate; [6-chloro-2-(4-chloropyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; [6-chloro-2-(pyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; [5-chloro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; methyl [5-chloro2-(6-methylpyridine -2-carbonyl)-1H-indol-3-yl]acetate; [5-chloro-2-(6-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; [6-chloro-2-(1-methylimidazole-2-carbonyl)-1H-indol-3-yl]acetic acid; methyl [5-chloro-2-(thiazole-2-carbonyl)-1H-indol-3-yl]acetate; [5-chloro-2-(thiazole-2-carbonyl)-1H-indol-3-yl]acetic acid; methyl(2-benzoyl-6-chloro-1H-indol-3-yl)acetate; (2-benzoyl-6-chloro-1H-indol-3-yl)-N,N-dimethylacetamide; (2-benzoyl-6-chloro-1H-indol-3-yl)-N-methylacetamide; (2-benzoyl-6-chloro-1H-indol-3-yl)acetamide; (2-benzoyl-6-chloro-1H-indol-3-yl)-N-methoxy-N-methylacetamide; 2-(2-benzoyl-6-chloro-1H-indol-3-yl)-1-piperidino-1-ethanone; 2-(2-benzoyl-6-chloro-1H-indol-3-yl)-1-(4-methyl-1-piperazinyl)-1-ethanone; 2-benzoyl-6-chloro-1H-indol-3-yl)-N-(2-cyanoethyl)acetamide; (2-benzoyl-6-chloro-1H-indol-3-yl)-N-(2-hydroxyethyl)acetamide; 2-(2-benzoyl-6-chloro-1H-indol-3-yl)-1-morpholino-1-ethanone; [2-(4-chlorobenzoyl)-1H-indol-3-yl]acetic acid; [6-chloro-2-(2-furylcarbonyl)-1H-indol-3-yl]acetic acid; [6-chloro-2-(cyclohexanecarbonyl)-1H-indol-3-yl]acetic acid; methyl [6-chloro-2-(4-methoxybenzoyl)-1H-indol-3-yl]acetate; [6-chloro-2-(4-methoxybenzoyl)-1H-indol-3-yl]acetic acid; methyl [6-chloro-2-(4-ethylpyridine-2-carbonyl)-1H-indol-3-yl]acetate; [6-chloro-2-(4-ethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; methyl [5-chloro-2-(4-ethylpyridine-2-carbonyl)-1H-indol-3-yl]acetate; [5-chloro-2-(4-ethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; methyl [6-chloro-2-(4-isopropylpyridine-2-carbonyl)-1H-indol-3-yl]acetate; [6-chloro-2-(4-isopropylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; methyl [5-chloro-2-(4-isopropylpyridine-2-carbonyl)-1H-indol-3-yl]acetate; [5-chloro-2-(4-isopropylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; methyl [6-chloro-2-(4-propylpyridine-2-carbonyl)-1H-indol-3-yl]acetate; [6-chloro-2-(2-(4-propylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; methyl [5-chloro-2-(4-propylpyridine-2-carbonyl)-1H-indol-3-yl]acetate; [5-chloro-2-(4-propylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; methyl [2-(4-tert-butylpyridine-2-carbonyl)-6-chloro-1H-indol-3-yl]acetate; [2-(4-tert-butylpyridine-2-carbonyl)-6-chloro-1H-indol-3-yl]acetic acid; methyl [2-(4-tert-butylpyridine-2-carbonyl)-5-chloro-1H-indol-3-yl]acetate; [2-(4-tert-butylpyridine-2-carbonyl)-5-chloro-1H-indol-3-yl]acetic acid; methyl [6-chloro-2-(3-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetate; [6-chloro-2-(3-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; methyl [5-chloro-2-(3-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetate; [5-chloro-2-(3-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; methyl [6-chloro-2-(6-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetate; [6-chloro-2-(6-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; methyl [5-chloro-2-(5-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetate; [5-chloro-2-(5-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; methyl [6-chloro-2-[5-(trifluoromethyl)pyridine-2-carbonyl]-1H-indol-3-yl]acetate; [6-chloro-2-(5-(trifluoromethyl)pyridine-2-carbonyl]-1H-indol-3-yl]acetic acid; methyl [5-chloro-2-[5-(trifluoromethyl)pyridine-2-carbonyl]-1H-indol-3-yl]acetate; [5-chloro-2-[5-(trifluoromethyl)pyridine-2-carbonyl]-1H-indol-3-yl]acetic acid; methyl [5-chloro-2-(5-chloropyridine-2-carbonyl)-1H-indol-3-yl]acetate; [5-chloro-2-(5-chloropyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; methyl [6-chloro-2-(5-chloropyridine-2-carbonyl)-1H-indol-3-yl]acetate; [6-chloro-2-(5-chloropyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; methyl [5-chloro-2-(4-chloropyridine-2-carbonyl)-1H-indol-3-yl]acetate; [5-chloro-2-(4-chloropyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; methyl [6-chloro-2-(pyridine-3-carbonyl)-1H-indol-3-yl]acetate; [6-chloro-2-(pyridine-3-carbonyl)-1H-indol-3-yl]acetic acid; methyl [6-chloro-2-(pyridine-4-carbonyl)-1H-indol-3-yl]acetate; [6-chloro-2-(pyridine-4-carbonyl)-1H-indol-3-yl]acetic acid; methyl [6-chloro-2-[4-(hydroxymethyl)pyridine-2-carbonyl]-1H-indol-3-yl]acetate; [6-chloro-2-[4-(hydroxymethyl)pyridine-2-carbonyl]-1H-indol-3-yl]acetic acid; methyl [5-chloro-2-[4-(hydroxymethyl)pyridine-2-carbonyl]-1H-indol-3-yl]acetate; [5-chloro-2-[4-(hydroxymethyl)pyridine-2-carbonyl]-1H-indol-3-yl]acetic acid; methyl [5-chloro-2-(3,4-dimethylpyridine-2-carbonyl)-1H-indol-3-yl]acetate; [5-chloro-2-(3,4-dimethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; methyl [5-chloro-2-(4,5-dimethylpyridine-2-carbonyl)-1H-indol-3-yl]acetate; [5-chloro-2-(4,5-dimethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; methyl [6-chloro-2-(4,5-dimethylpyridine-2-carbonyl)-1H-indol-3-yl]acetate; [6-chloro-2-(4,5-dimethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; methyl [6-chloro-2-(4-methoxypyridine-2-carbonyl)-1H-indol-3-yl]acetate; [6-chloro-2-(4-methoxypyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; methyl [5-chloro-2-(4-methoxypyridine-2-carbonyl)-1H-indol-3-yl]acetate; [5-chloro-2-(4-methoxypyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; methyl [6-chloro-2-(3,5-dimethylpyridine-2-carbonyl)-1H-indol-3-yl]acetate; [6-chloro-2-(3,5-dimethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; methyl [5-chloro-2-(4-ethyl-3-fluoropyridine-2-carbonyl)-1H-indol-3-yl]acetate; [5-chloro-2-(4-ethyl-3-fluoropyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; methyl [6-chloro-2-(4-ethyl-3-fluoropyridine-2-carbonyl)-1H-indol-3-yl]acetate; [6-chloro-2-(3-ethoxy-4-ethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; methyl [6-chloro-2-(3-chloro-4-ethylpyridine-2-carbonyl)-1H-indol-3-yl]acetate; [6-chloro-2-(3-chloro-4-ethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; methyl [5-chloro-2-(3-chloro-4-ethylpyridine-2-carbonyl)-1H-indol-3-yl]acetate; [5-chloro-2-(3-chloro-4-ethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; methyl [5-chloro-2-(4,6-dimethylpyridine-2-carbonyl)-1H-indol-3-yl]acetate; [5-chloro-2-(4,6-dimethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; methyl [6-chloro-2-(4,6-dimethylpyridine-2-carbonyl)-1H-indol-3-yl]acetate; [6-chloro-2-(4,6-dimethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; methyl [5,6-dichloro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetate; [5,6-dichloro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; methyl [5-methyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetate; [5-methyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; methyl [5-fluoro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetate; [5-fluoro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; methyl [5-methoxy-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetate; [5-methoxy-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; methyl [6-methoxy-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetate; [6-methoxy-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; methyl [5-ethyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetate; [5-ethyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; methyl [5-ethyl-2-(4-ethylpyridine-2-carbonyl)-1H-indol-3-yl]acetate; [5-ethyl-2-(4-ethylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; methyl [6-ethyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetate; [6-ethyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; methyl [5-isopropyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetate; [5-isopropyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; methyl [2-(4-methylpyridine-2-carbonyl)-6-trifluoromethyl-1H-indol-3-yl]acetate; [2-(4-methylpyridine-2-carbonyl)-6-trifluoromethyl-1H-indol-3-yl]acetic acid; methyl [5-tert-butyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetate; [5-tert-butyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; methyl [2-(4-methylpyridine-2-carbonyl)-5-trifluoromethoxy-1H-indol-3-yl]acetate; [2-(4-methyl-2-pyridine-2-carbonyl)-5-trifluoromethoxy-1H-indol-3-yl]acetic acid; methyl [2-(4-ethylpyridine-2-carbonyl)-5-trifluoromethoxy-1H-indol-3-yl]acetate; [2-(4-ethylpyridine-2-carbonyl)-5-trifluoromethoxy-1H-indol-3-yl]acetic acid; methyl [6-methyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetate; [6-methyl-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; methyl [2-(4-methylpyridine-2-carbonyl)-5-trifluoromethyl-1H-indol-3-yl]acetate; [2-(4-methylpyridine-2-carbonyl)-5-trifluoromethyl-1H-indol-3-yl]acetic acid; methyl [2-(4-ethylpyridine-2-carbonyl)-5-trifluoromethyl-1H-indol-3-yl]acetate; [2-(4-ethylpyridine-2-carbonyl)-5-trifluoromethyl-1H-indol-3-yl]acetic acid; methyl (2-benzoyl-1H-indol-3-yl)acetate; (2-benzoyl-1H-indol-3-yl)acetic acid; methyl [2-(4-chlorobenzoyl)-6-methyl-1H-indol-3-yl]acetate; [2-(4-chlorobenzoyl)-6-methyl-1H-indol-3-yl]acetic acid; [2-(4-chlorobenzoyl)-5-methyl-1H-indol-3-yl]acetic acid; methyl [6-methoxy-2-(4-chlorobenzoyl)-1H-indol-3-yl]acetate; [6-methoxy-2-(4-chlorobenzoyl)-1H-indol-3-yl]acetic acid; [2-(4-chlorobenzoyl)-6-trifluoromethyl-1H-indol-3-yl]acetic acid; methyl [2-(4-chlorobenzoyl)-5-ethyl-1H-indol-3-yl]acetate; [2-(4-chlorobenzoyl)-5-ethyl-1H-indol-3-yl]acetic acid; methyl [2-(4-chlorobenzoyl)-5-methoxy-1H-indol-3-yl]acetate; [2-(4-chlorobenzoyl)-5-methoxy-1H-indol-3-yl]acetic acid; methyl [2-(4-chlorobenzoyl)-5-isopropyl-1H-indol-3-yl]acetate; [2-(4-chlorobenzoyl)-5-isopropyl-1H-indol-3-yl]acetic acid; methyl [2-(4-chlorobenzoyl)-5-trifluoromethyl-1H-indol-3-yl]acetate; [2-(4-chlorobenzoyl)-5-trifluoromethyl-1H-indol-3-yl]acetic acid; methyl [2-(4-chlorobenzoyl)-5-trifluoromethoxy-1H-indol-3-yl]acetate; [2-(4-chlorobenzoyl)-5-trifluoromethoxy-1H-indol-3-yl]acetic acid; methyl [6-chloro-2-(2-methoxybenzoyl)-1H-indol-3-yl]acetate; [6-chloro-2-(2-methoxybenzoyl)-1H-indol-3-yl]acetic acid; methyl [6-chloro-2-(3-methoxybenzoyl)-1H-indol-3-yl]acetate; [6-chloro-2-(3-methoxybenzoyl)-1H-indol-3-yl]acetic acid; methyl [6-chloro-2-(3-benzyloxybenzoyl)-1H-indol-3-yl]acetate; [6-chloro-2-(3-benzyloxybenzoyl)-1H-indol-3-yl]acetic acid; methyl [6-chloro-2-(3-hydroxybenzoyl)-1H-indol-3-yl]acetate; [6-chloro-2-(3-hydroxybenzoyl)-1H-indol-3-yl]acetic acid; methyl [6-chloro-2-(4-benzoxybenzyloyl)-1H-indol-3-yl]acetate; [6-chloro-2-(4-benzyloxybenzoyl)-1H-indol-3-yl]acetic acid; methyl [6-chloro-2-(4-hydroxybenzoyl)-1H-indol-3-yl]acetate; [6-chloro-2-(4-hydroxybenzoyl)-1H-indol-3-yl]acetic acid; methyl [6-chloro-2-(4-isopropoxybenzoyl)-1H-indol-3-yl]acetate; [6-chloro-2-(4-isopropoxybenzoyl)-1H-indol-3-yl]acetic acid; methyl [6-chloro-2-(4-phenylbenzoyl)-1H-indol-3-yl]acetate; [6-chloro-2-(4-phenylbenzoyl)-1H-indol-3-yl]acetic acid; methyl [6-chloro-2-(4-trifluoromethoxybenzoyl)-1H-indol-3-yl]acetate; [6-chloro-2-(4-trifluoromethoxybenzoyl)-1H-indol-3-yl]acetic acid; methyl [5-chloro-2-(4-trifluoromethoxybenzoyl)-1H-indol-3-yl]acetate; [5-chloro-2-(4-trifluoromethoxybenzoyl)-1H-indol-3-yl]acetic acid; methyl [5-chloro-2-(4-methoxybenzoyl)-1H-indol-3-yl]acetate; [5-chloro-2-(4-methoxybenzoyl)-1H-indol-3-yl]acetic acid; methyl [6-chloro-2-(4-nitrobenzoyl)-1H-indol-3-yl]acetate; [6-chloro-2-(4-nitrobenzoyl)-1H-indol-3-yl]acetic acid; methyl [6-chloro-2-[(4-methylsulfonyl)benzoyl]-1H-indol-3-yl]acetate; [6-chloro-2-[(4-methylsulfonyl)benzoyl]-1H-indol-3-yl]acetic acid; methyl [6-chloro-2-[4-(methylsulfonylamino)benzoyl]-1H-indol-3-yl]acetate; [6-chloro-2-[4-(methylsulfonylamino)benzoyl]-1H-indol-3-yl]acetic acid; [6-chloro-2-(2-chlorobenzoyl)-1H-indol-3-yl]acetic acid; [6-chloro-2-(2,4-dichlorobenzoyl)-1H-indol-3-yl]acetic acid; methyl [6-chloro-2-(4-chloro-3-fluorobenzoyl)-1H-indol-3-yl]acetate; [6-chloro-2-(4-chloro-3-fluorobenzoyl)-1H-indol-3-yl]acetic acid; methyl [6-chloro-2-(4-cyanobenzoyl)-1H-indol-3-yl]acetate; methyl [6-chloro-2-[4-bromobenzoyl]-1H-indol-3-yl]acetate; methyl [6-chloro-2-[4-(2-thienyl)benzoyl]-1H-indol-3-yl]acetate; [6-chloro-2-[4-(2-thienyl)benzoyl]-1H-indol-3-yl]acetic acid; methyl [6-chloro-2-[4-(2-furyl)benzoyl]-1H-indol-3-yl]acetate; [6-chloro -2-[4-(2-furyl)benzoyl]-1H-indol-3-yl]acetic acid; methyl [6-chloro-2-[4-(3-pyridyl)benzoyl]-1H-indol-3-yl]acetate; [6-chloro-2-[4-(3-pyridyl)benzoyl]-1H-indol-3-yl]acetic acid; methyl [6-chloro-2-[4-(2-thiazolyl)benzoyl]-1H-indol-3-yl]acetate; [6-chloro-2-[4-(2-thiazolyl)benzoyl]-1H-indol-3-yl]acetic acid; methyl [6-chloro-2-(3-bromobenzoyl)-1H-indol-3-yl]acetate; methyl [6-chloro-2-[3-(2-furyl)benzoyl]-1H-indol-5 3-yl]acetate; [6-chloro-2-[3-(2-furyl)benzoyl]-1H-indol-3-yl]acetic acid; methyl dl-2-[6-chloro-2-(4-chlorobenzoyl)-1H-indol-3-yl]propionate; dl-2-[2-(4-chlorobenzoyl)-6-chloro-1H-indol-3-yl]propionic acid; methyl [5-chloro-2-(isoquinoline-3-carbonyl)-1H-indol-3-yl]acetate; [5-chloro-2-(isoquinoline-3-carbonyl)-1H-indol-3-yl]acetic acid; methyl [6-chloro-2-(isoquinoline-3-carbonyl)-1H-indol-3-yl]acetate; [6-chloro-2-(isoquinoline-3-carbonyl)-1H-indol-3-yl]acetic acid; methyl [5-chloro-2-(5-methylisoxazole-3-carbonyl)-1H-indol-3-yl]acetate; [5-chloro-2-(5-methylisoxazole-3-carbonyl)-1H-indol-3-yl]acetic acid; methyl [6-chloro-2-(5-methylisoxazole-3-carbonyl)-1H-indol-3-yl]acetate; [6-chloro-2-(5-methylisoxazole-3-carbonyl)-1H-indol-3-yl]acetic acid; methyl [5-chloro-2-(4-methyl-1 ,2,3-thiadiazole-5-carbonyl)-1H-indol-3-yl]acetate; [5-chloro-2-(4-methyl-1,2,3-thiadiazole-5-carbonyl)-1H-indol-3-yl]acetic acid; methyl [6-chloro-2-(4-methyl-1 ,2,3-thiadiazole-5-carbonyl)-1H-indol-3-yl]acetate; [6-chloro-2-(4-methyl-1 ,2,3-thiadiazole-5-carbonyl)-1H-indol-3-yl]acetic acid; methyl [5-chloro-2-(5-methylthiazole-2-carbonyl)-1H-indol-3-yl]acetate; [5-chloro-2-(5-methylthiazole-2-carbonyl)-1H-indol-3-yl]acetic acid; methyl [6-chloro-2-(5-methylthiazole-2-carbonyl)-1H-indol-3-yl]acetate; [6-chloro-2-(5-methylthiazole-2-carbonyl)-1H-indol-3-yl]acetic acid; [6-chloro-2-(2-thienyl)carbonylindol-3-yl]acetic acid; methyl [6-chloro-2-[3-(1-hydroxy-1-methylethyl)-2-furoyl]-1H-indol-3-yl]acetate [6-chloro-2-[3-(1-hydroxy-1-methylethyl)-2-furoyl]-1H-indol-3-yl]acetic acid; methyl [6-chloro-2-[3-methoxymethyl-2-furoyl]-1H-indol-3-yl]acetate; [6-chloro-2-[3-methoxymethyl-2-furoyl]-1H-indol-3-yl]acetic acid; [6-chloro-2-(1-methylimidazole-2-carbonyl)-1H-indol-3-yl]acetic acid; methyl [6-chloro-2-(1-methylimidazole-2-carbonyl)-1H-indol-3-yl]acetate; methyl [5-chloro-2-(1-methylimidazole-2-carbonyl)-1H-indol-3-yl]acetate; [5-chloro-2(1-methylimidazole-2-carbonyl)-1H-indol-3-yl]acetic acid; methyl [5-chloro-2-(imidazole-2-carbonyl)-1H-indol-3-yl]acetate; [5-chloro-2-(imidazole-2-carbonyl)-1H-indol-3-yl]acetic acid; methyl [6-chloro-2-(imidazole-2-carbonyl)-1H-indol-3-yl]acetate; [6-chloro-2-(imidazole-2-carbonyl)-1H-indol-3-yl]acetic acid; methyl [5-chloro-2-(4-methylthiazole-2-carbonyl)-1H-indol-3-yl]acetate; [5-chloro-2-(4-methylthiazole-2-carbonyl)-1H-indol-3-yl]acetic acid; methyl [5-chloro-2-(1-methylpyrrole-2-carbonyl)-1H-indol-3-yl]acetate; [5-chloro-2-(1-methylpyrrole-2-carbonyl)-1H-indol-3-yl]acetic acid; methyl [5-chloro-2-(2-methylimidazole-4-carbonyl)-1H-indol-3-yl]acetate; [5-chloro-2-(2-methylimidazole-4-carbonyl)-1H-indol-3-yl]acetic acid; methyl [5-chloro-2-(thiazole-5-carbonyl)-1H-indol-3-yl]acetate; [5-chloro-2-(thiazole-5-carbonyl)-1H-indol-3-yl]acetic acid; methyl [6-chloro-2-(4-methylthiazole-2-carbonyl)-1H-indol-3-yl]acetate; [6-chloro-2-(4-methylthiazole-2-carbonyl)-1H-indol-3-yl]acetic acid; methyl [5-chloro-2-[3-(ethoxycaronyl)isoxazole-5-carbonyl]-1H-indol-3-yl]acetate; [5-chloro-2-[3-(carboxy)isoxazole-5-carbonyl]-1H-indol-3-yl]acetic acid; methyl [6-chloro-2-cyclopropanecarbonyl-1H-indol-3-yl]acetate; [6-chloro-2-cyclopropanecarbonyl-1H-indol-3-yl]acetic acid; methyl [6-chloro-2-cyclobutanecarbonyl-1H-indol-3-yl]acetate; [6-chloro-2-cyclobutanecarbonyl-1H-indol-3-yl]acetic acid; methyl [5-(tert-butyl)-2-(4-chlorobenzoyl)-1H-indol-3-yl]acetate; [5-(tert-butyl)-2-(4-chlorobenzoyl)-1H-indol-3-yl]acetic acid; [6-chloro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]-N,N-dimethylacetamide; [6-chloro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]-N-methylacetamide; [5-chloro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]-N-(2-hydroxyethyl)acetamide; [5-chloro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]-N-methoxyacetamide; 2-[5-chloro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]-1-piperazinyl-1-ethanone; [5-chloro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]-N-(2-aminoethyl)acetamide; 2-[5-chloro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]-1-(3-amino-1-pyrrolidinyl)-1-ethanone; [6-chloro-2-(4-chlorobenzoyl)-5-fluoro-1H-indol-3-yl]acetic acid; methyl [6-chloro-5-fluoro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetate; [6-chloro-5-fluoro-2-(4-methylpyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; methyl [6-chloro-2-[4-(1-hydroxyethyl)pyridine-2-carbonyl]-1H-indol-3-yl]acetate; [6-chloro-2-[4-(1-hydroxyethyl)pyridine-2-carbonyl]-1H-indol-3-yl]acetic acid; [6-chloro-2-(4-ethyl-3-fluoropyridine-2-carbonyl)-1H-indol-3-yl]acetic acid; [6-chloro-2-(2-nitrobenzoyl)-1H-indol-3-yl]acetic acid; [6-chloro-2-(2,4-dimethoxybenzoyl)-1H-indol-3-yl]acetic acid; [6-chloro-2-(4-difuluoromethoxybenzoyl)-1H-indol-3-yl]acetic acid; [6-chloro-2-(2,5-dimethoxybenzoyl)-1H-indol-3-yl]acetic acid; methyl [5-acetyl-2-(4-chlorobenzoyl)-1H-indol-3-yl]acetate; [5-acetyl-2-(4-chlorobenzoyl)-1H-indol-3-yl]acetic acid; methyl [6-chloro-2-(4-chlorobenzoyl)-5-fluoro-1H-indol-3-yl]acetate; methyl [6-fluoro-2-(4-methylpridine-2-carbonyl]-1H-indol-3-yl]acetate; [6-fluoro-2-(4-methylpridine-2-carbonyl)-1H-indol-3-yl]acetic acid; methyl [6-fluoro-2-(4-chlorobenzoyl)-1H-indol-3-yl]acetate; [6-fluoro-2-(4-chlorobenzoyl)-1H-indol-3-yl]acetic acid; [2-(4-methylpyridine-2-carbonyl)-5-methylthio-1H-indol-3-yl]acetic acid; 2-(5H)-furanone, 4-[4(methylsulfonyl)phenyl]-3-phenyl-(rofecoxib); [2-(4-methylpyridine-2-carbonyl)-5-methylthio-1H-indol-3-yl]acetic acid; a prodrug thereof or a pharmaceutically acceptable salt thereof or of said prodrug. It is particularly preferred that the selective COX-2 inhibitor is rofecoxib, which has the following chemical structure: 
This invention is also directed to methods of treating a diabetic complication in a mammal comprising administering to said mammal a pharmaceutical composition as set forth hereinabove. In particular, such diabetic complications as, for example, diabetic neuropathy, diabetic nephropathy, diabetic cardiomyopathy, myocardial infarction, cataracts and diabetic retinopathy can be treated by the methods of this invention.
This invention is also directed to methods of treating a diabetic complication in a mammal suffering from a diabetic complication comprising administering to said mammal an ARI, a prodrug thereof or a pharmaceutically acceptable salt of said ARI or said prodrug; and
(a) a selective cyclooxygenase-2 (COX-2) inhibitor of formula I, 
xe2x80x83a prodrug thereof or a pharmaceutically acceptable salt thereof or of said prodrug,
xe2x80x83wherein the variables of the compound of formula I are defined as follows:
R1 is hydrogen or (C1-C4)alkyl; R2 is C(xe2x95x90Lxe2x80x2)R3 or SO2R4; Y is a direct bond or (C1-C4)alkylene; L and Lxe2x80x2 are independently oxygen or sulfur;
Q is selected from the following:
(Q-a) (C1-C6)alkyl;
(Q-b) halo-substituted (C1-C4)alkyl;
(Q-c) (C3-C7)cycloalkyl optionally substituted with one or two substituents independently selected from (C1-C4)alkyl, halo-substituted (C1-C4)alkyl, (C1-C4)alkoxy, hydroxy and halo;
(Q-d) phenyl or naphthyl, the phenyl and naphthyl being optionally substituted with one, two or three substituents independently selected from halo, (C1-C4)alkyl, halo-substituted (C1-C4)alkyl, hydroxy, (C1-C4)alkoxy, nitro, halo-substituted (C1-C4)alkoxy, S(O)mR5 SO2NH2, SO2N(C1-4 alkyl)2, amino, (C1-C4)alkylamino, di-((C1-C4)alkyl)amino, NR1C(O)R5, CN, (C1-C4)alkyl-OH and (C1-C4)alkyl-OR5;
(Q-e) a 5-membered monocyclic aromatic group containing one heteroatom selected from O, S and N and optionally containing one, two or three nitrogen atom(s) in addition to said heteroatom, and said monocyclic aromatic group being optionally substituted with one, two or three substituents independently selected from halo, (C1-C4)alkyl, halo-substituted (C1-C4)alkyl, hydroxy, (C1-C4)alkoxy, halo-substituted (C1-C4)alkoxy, amino, C1-4 alkylamino, di-((C1-C4)alkyl)amino, (C1-C4)alkyl-OH and (C1-C4)alkyl-OR5; and
(Q-f) a 6-membered monocyclic aromatic group containing one nitrogen atom and optionally containing one, two or three additional nitrogen atom(s), and said monocyclic aromatic group being optionally substituted with one, two or three substituents independently selected from halo, (C1-C4)alkyl, halo-substituted (C1-C4)alkyl, hydroxy, (C1-C4)alkoxy, halo-substituted (C1-C4)alkoxy, amino, (C1-C4)alkylamino, di-((C1-C4)alkyl)amino, (C1-C4)alkyl-OH and (C1-C4)alkyl-OR5;
R3 is xe2x80x94OR6, xe2x80x94NR7R8, N(OR1)R7 or a group of formula: 
xe2x80x83Z is a direct bond, oxygen, sulfur or NR5;
R4 is (C1-C6)alkyl, halo-substituted (C1-C4)alkyl, (C1-C4)alkyl-OH, xe2x80x94NR7R8, phenyl or naphthyl, the phenyl and naphthyl being optionally substituted with one, two or three substituents independently selected from halo, (C1-C4)alkyl, halo-substitutued (C1-C4)alkyl, hydroxy, (C1-C4)alkoxy and halo-substitutued (C1-C4)alkoxy;
R5 is (C1-C4)alkyl or halo-substituted (C1-C4)alkyl;
R6 is (C1-C4)alkyl, (C3-C7)cycloalkyl, (C1-C4)alkyl-(C3-C7)cycloalkyl, halo-substitutued (C1-C4)alkyl, (C1-C4)alkyl-phenyl or phenyl, the phenyl moiety being optionally substituted with one, or two substituents independently selected from halo, (C1-C4)alkyl, halo-substitutued (C1-C4)alkyl, hydroxy, (C1-C4)alkoxy, (C1-C4)alkylthio, amino, di-((C1-C4)alkyl)amino and nitro;
R7 and R8 are independently selected from I hydrogen, (ii) (C1-C6)alkyl optionally substituted with a substituent independently selected from halo, hydroxy, (C1-C4)alkoxy, amino, (C1-C4)alkylamino and di-((C1-C4)alkyl)amino, (iii) (C3-C7)cycloalkyl optionally substituted with a substituent independently selected from hydroxy, (C1-C4)alkyl and (C1-C4)alkoxy, (iv) (C1-C4)alkyl-(C3-C7)cycloalkyl optionally substituted with a substituent independently selected from hydroxy, (C1-C4)alkyl and (C1-C4)alkoxy, and (v) (C1-C4)alkyl-phenyl or phenyl, the phenyl moiety being optionally substituted with one or two substituents independently selected from halo, (C1-C4)alkyl, halo-substitutued (C1-C4)alkyl, hydroxy, (C1-C4)alkoxy, (C1-C4)alkylthio, nitro, amino, di-((C1-C4)alkyl)amino and CN;
X is independently selected from halo, (C1-C4)alkyl, halo-substitutued (C1-C4)alkyl, hydroxy, (C1-C4)alkoxy, halo-substitutued (C1-C4)alkoxy, (C1-C4)alkylthio, nitro, amino, di-((C1-C4)alkyl)amino and CN;
m is 0, 1 or 2; n is 0, 1, 2 or 3; and r is 1, 2 or 3; or
(b) a selective COX-2 inhibitor of formula XX, 
xe2x80x83a prodrug thereof or a pharmaceutically acceptable salt thereof or of said prodrug,
xe2x80x83wherein the variables of the compound of formula XX are defined as follows:
A is a partially unsaturated or unsaturated five membered heterocyclic, or a partially unsaturated or unsaturated five membered carbocyclic, wherein the 4-(sulfonyl)phenyl and the 4-substituted phenyl in the formula XX are attached to ring atoms of Ring A adjacent to each other;
R1 is aryl or heteroaryl, and the aryl or heteroaryl being optionally substituted by one to four substituents selected from halo, (C1-C4)alkyl, halo-substituted (C1-C4)alkyl, (C1-C4)alkoxy, (C1-C4)alkyl carbonyl, hydroxy, nitro, cyano and amino, with the proviso that when A is pyrazole, R1 is heteroaryl;
R2 is (C1-C4)alkyl, halo-substituted (C1-C4)alkyl, (C1-C4)alkylamino, (C1-C4)dialkylamino or amino;
R3, R4 and R5 are independently hydrogen, halo, (C1-C4)alkyl, halo-substituted (C1-C4)alkyl, (C2-C5)alkenyl, (C2-C5)alkynyl, (C1-C4)alkoxy, hydroxy-(C1-C4)alkyl, (C1-C4)alkoxy (C1-C4)alkyl, (C1-C4)alkanoyl, cyano, nitro, cyano (C1-C4)alkyl, carboxy, (C1-C4)alkoxycarbonyl, aminocarbonyl, N-(C1-C4)alkylaminocarbonyl, N,N-di-(C1-C4)alkylaminocarbonyl, N-arylaminocarbonyl, N,N-diarylaminocarbonyl, N-(C1-C4)alkyl-N-arylaminocarbonyl, aryl, aryloxy, aryloxy-(C1-C4)alkyl, heteroaryl, heteroaryloxy, heteroaryloxy-(C1-C4)alkyl, morpholino-carbonyl, (C1-C4)alkoxyaminocarbonyl or (C1-C4)alkyl-carbonylamino; or two of R3, R4 and R5 are taken together with atoms to which they are attached and form a 4-7 membered ring;
R6 and R7 are independently hydrogen, halo, (C1-C4)alkyl, halo-substituted (C1C4)alkyl, (C1-C4)alkoxy, (C1-C4)alkylthio, (C1-C4)alkylamino, N,N-di (C1-C4)alkylamino, hydroxyl-(C1-C4)alkyl, (C1-C4)alkoxy-(C1-C4)alkyl, (C1-C4)alkyl-(C1-C4)alkoxy, (C1-C4)alkylamino-(C1-C4)alkyl, hydroxy, amino-(C1-C4)alkyl and N,N-di (C1-C4)alkylamino-(C1-C4)alkyl; and
m and n are independently 1, 2, 3 or 4,
with the proviso that when A contains an oxygen or sulfur heteroatom, one of R3, R4 or R5 is absent; or
(c) a selective COX-2 inhibitor of formula XXX, 
xe2x80x83a prodrug thereof or a pharmaceutically acceptable salt thereof or of said prodrug,
xe2x80x83wherein variables of the compound of formula XXX are defined as follows:
Ar is heteroaryl selected from a 5-membered monocyclic aromatic ring having one hetero atom selected from O, S and N and optionally containing one to three N atom(s) in addition to said hetero atom, or a 6-membered monocyclic aromatic ring having one N atom and optionally containing one to four N atom(s) in addition to said N atom; and said heteroaryl being connected to the nitrogen atom on the benzimidazole through a carbon atom on the heteroaryl ring;
X1 is independently selected from halo, (C1-C4)alkyl, hydroxy, (C1-C4)alkoxy, halo-substituted (C1-C4)alkyl, hydroxy-substituted (C1-C4)alkyl, ((C1-C4)alkoxy)(C1-4)alkyl, halo-substituted (C1-C4)alkoxy, amino, Nxe2x80x94((C1-C4)alkyl)amino, N,N-di((C1-C4)alkyl)amino, [Nxe2x80x94((C1-C4)alkyl)amino](C1-C4)alkyl, [N,N-di((C1-C4)alkyl)amino](C1-C4)alkyl, Nxe2x80x94((C1-C4)alkanoyl)amino, Nxe2x80x94((C1-C4)alkyl)-Nxe2x80x94((C1-C4)alkanoyl)amino, Nxe2x80x94[((C1-C4)alkyl)sulfonyl]amino, N-[(halo-substituted (C1-C4)alkyl)sulfonyl]amino, (C1-C4)alkanoyl, carboxy, ((C1-C4)alkoxy)carbonyl, carbamoyl, [Nxe2x80x94((C1-C4)alkyl)amino]carbonyl, [N,N-di((C1-C4)alkyl)amino]carbonyl, cyano, nitro, mercapto, ((C1-C4)alkyl)thio, ((C1-C4)alkyl)sulfinyl, ((C1-C4)alkyl)sulfonyl, aminosulfonyl, [Nxe2x80x94((C1-C4)alkyl)amino]sulfonyl and [N,N-di((C1-C4)alkyl)amino]sulfonyl;
X2 is independently selected from halo, (C1-C4)alkyl, hydroxy, (C1-C4)alkoxy, halo-substituted (C1-C4)alkyl, hydroxy-substituted (C1-C4)alkyl, ((C1-C4)alkoxy)(C1-C4)alkyl, halo-substituted (C1-C4)alkoxy, amino, Nxe2x80x94((C1-C4))alkyl)amino, N,N-di((C1-C4)alkyl)amino, [Nxe2x80x94((C1-C4)alkyl)amino](C1-C4)alkyl, [N,N-di((C1-C4)alkyl)amino](C1-C4)alkyl, Nxe2x80x94((C1-C4)alkanoyl)amino, Nxe2x80x94((C1-C4)alkyl)-Nxe2x80x94((C1-C4)alkanoyl)amino, Nxe2x80x94[((C1-C4)alkyl)sulfonyl]amino, N-[(halo-substituted (C1-C4)alkyl)sulfonyl]amino, (C1-C4)alkanoyl, carboxy, ((C1-C4)alkoxy)carbonyl, carbamoyl, [Nxe2x80x94((C1-C4)alkyl)amino]carbonyl, [N,N-di((C1-C4)alkyl)amino]carbonyl, N-carbamoylamino, cyano, nitro, mercapto, (C1-C4)alkyl)thio, ((C1-C4)alkyl)sulfinyl, ((C1-C4)alkyl)sulfonyl, aminosulfonyl, [Nxe2x80x94((C1-C4)alkyl)amino]sulfonyl and [N,N-di((C1-C4)alkyl)amino]sulfonyl;
R1 is selected from
hydrogen;
straight or branched (C1-C4)alkyl optionally substituted with up to three substituents wherein said substituents are independently selected from halo, hydroxy, (C1-C4)alkoxy, amino, Nxe2x80x94((C1-C4)alkyl)amino and N,N-di((C1-C4)alkyl)amino;
(C3-C8)cycloalkyl optionally substituted with up to three substituents wherein said substituents are independently selected from halo, (C1-C4)alkyl, hydroxy, (C1-C4)alkoxy, amino, Nxe2x80x94((C1-C4)alkyl)amino and N,N-di((C1-C4)alkyl)amino;
(C4-C8) cycloalkenyl optionally substituted with up to three substituents wherein said substituents are independently selected from halo, (C1-C4)alkyl, hydroxy, (C1-C4)alkoxy, amino, Nxe2x80x94(C1-C4)alkyl)amino and N,N-di((C1-C4)alkyl)amino;
phenyl optionally substituted with up to three substituents wherein said substituents are independently selected from halo, (C1-C4)alkyl, hydroxy, (C1-C4)alkoxy, halo-substituted (C1-C4)alkyl, hydroxy-substituted (C1-C4)alkyl, ((C1-C4)alkoxy)(C1-C4)alkyl, halo-substituted (C1-C4)alkoxy, amino, Nxe2x80x94((C1-C4)alkyl)amino, N,N-di((C1-C4)alkyl)amino, [Nxe2x80x94((C1-C4)alkyl)amino](C1-C4)alkyl, [N,N-di((CC1-C4)alkyl)amino](C1-C4)alkyl, Nxe2x80x94((C1-C4)alkanoyl)amino, Nxe2x80x94[((C1-C4)alkyl)((C1-C4)alkanoyl)]amino, Nxe2x80x94[((C1-C4)alkyl)sulfonyl]amino, N-[(halo-substituted (C1-C4)alkyl)sulfonyl]amino, (C1-C4)alkanoyl, carboxy, ((C1-C4)alkoxy)carbonyl, carbamoyl, [Nxe2x80x94((C1-C4)alkyl)amino]carbonyl, [N,N-di((C1-C4)alkyl)amino]carbonyl, cyano, nitro, mercapto, ((C1-C4)alkyl)thio, ((C1-C4)alkyl)sulfinyl, ((C1-C4)alkyl)sulfonyl, aminosulfonyl, [Nxe2x80x94((C1-C4)alkyl)amino]sulfonyl and [N,N-di((C1-C4)alkyl)amino]sulfonyl; and
heteroaryl selected from
a 5-membered monocyclic aromatic ring having one hetero atom selected from O, S and N and optionally containing one to three N atom(s) in addition to said hetero atom; or
a 6-membered monocyclic aromatic ring having one N atom and optionally containing one to four N atom(s) in addition to said N atom; and
said heteroaryl is optionally substituted with up to three substituents selected from X1;
R2and R3 are independently selected from
hydrogen;
halo;
(C1-C4)alkyl;
phenyl optionally substituted with up to three substituents wherein said substituents are independently selected from halo, (C1-C4)alkyl, hydroxy, (C1-C4)alkoxy, amino, Nxe2x80x94((C1-C4)alkyl)amino and N,N-di((C1-C4)alkyl)amino;
m is 0, 1, 2, 3,4 or 5; and
n is 0,1, 2, 3, or 4; or
(d) a selective COX-2 inhibitor of formula XL, 
xe2x80x83a prodrug thereof or a pharmaceutically acceptable salt thereof or of said prodrug
xe2x80x83wherein the variables of the compound of formula XL are defined as follows:
Z is OH, (C1-C6)alkoxy, xe2x80x94NR2R3 or a group of formula II or formula III: 
xe2x80x83wherein r is 1, 2, 3 or 4, Y is a direct bond, O, S or NR4, and W is OH or xe2x80x94NR2R3;
Q is selected from the following:
(A) phenyl optionally substituted with one, two or three substituents independently selected from
I halo, (C1-C4)alkyl, halo-substituted (C1-C4)alkyl, OH, (C1-C4)alkoxy, halo-substituted (C1-C4)alkoxy, (C1-C4)alkylthio, NO2, NH2, di-((C1-C4)alkyl)amino, (C1-C4)alkylamino, CN, HOxe2x80x94(C1-C4)alkyl, (C1-C4)alkoxy-(C1-C4)alkyl, (C1-C4)alkylsulfonyl, aminosulfonyl, xe2x80x94NH2S(O)2NR2R3, acetyl, xe2x80x94COOH, xe2x80x94C(O)Oxe2x80x94(C1-C4)alkyl, (C1-C4)alkylsulfonylamino and (C3-C7)cycloalkyl;
(ii) aryl or xe2x80x94Oxe2x80x94(CH2)n-aryl, wherein either aryl moiety is optionally substituted with one, two or three substituents independently selected from halo, (C1-C4)alkyl, halo-substituted (C1-C4)alkyl, OH, (C1-C4)alkoxy, halo-substituted (C1-C4)alkoxy, (C1-C4)alkylthio, NO2, NH2, di-(((C1-C4)alkyl)amino, (C1-C4)alkylamino and CN;
(iii) 5-membered monocyclic aromatic group optionally substituted with one, two or three substituents independently selected from halo, (C1-C4)alkyl, halo-substituted (C1-C4)alkyl, OH, (C1-C4)alkoxy, halo-substituted (C1-C4)alkoxy, (C1-C4)alkylthio, NO2, NH2, di-((C1-C4)alkyl)amino, (C1-C4)alkylamino and CN;
(iv) 6-membered monocyclic aromatic group optionally substituted with one, two or three substituents independently selected from halo, (C1-C4)alkyl, halo-substituted (C1-C4)alkyl, OH, (C1-C4)alkoxy, halo-substituted (C1-C4)alkoxy, (C1-C4)alkylthio, NO2, NH2, di-((C1-C4)alkyl)amino, (C1-C4)alkylamino and CN;
(B) a 6-membered monocyclic aromatic group containing one, two, three or four nitrogen atom(s), and said monocyclic aromatic group being optionally substituted with one, two or three substituents independently selected from the above group i, ii, iii and iv;
(C) a 5-membered monocyclic aromatic group containing one heteroatom selected from O, S and N and optionally containing one, two or three nitrogen atom(s) in addition to said heteroatom, and said monocyclic aromatic group being optionally substituted with one, two or three substituents independently selected from the above group i, ii, iii and iv;
(D) (C3-C7)cycloalkyl optionally substituted with one or two substituents independently selected from OH, (C1-C4)alkyl, halo and halo-substituted (C1-C4)alkyl; and
(E) a benzo-f used heterocycle optionally substituted with one, two or three substituents independently selected from the group (a-1);
R1 is hydrogen, (C1-C4)alkyl or halo;
R2 and R3 are independently H, OH, (C1-C4)alkoxy, (C1-C4)alkyl or (C1-C4)alkyl substituted with halo, OH, (C1-C4)alkoxy, NH2 or CN;
R4 is hydrogen or (C1-C4)alkyl;
X is independently selected from halo, (C1-C4)alkyl, halo-substituted (C1-C4)alkyl, OH, (C1-C4)alkoxy, halo-substituted (C1-C4)alkoxy, (C1-C4)alkylthio, NO2, NH2, di-((C1-C4)alkyl)amino, (C1-C4)alkylamino, CN, HOxe2x80x94(C1-C4)alkyl, (C1-C4)alkoxy-(C1-C4)alkyl, (C1-C4)alkylsulfonyl, aminosulfonyl, xe2x80x94NH2S(O)2NR2NR3, acetyl, xe2x80x94COOH, xe2x80x94C(O)Oxe2x80x94(C1-C4)alkyl, (C1-C4)alkylsulfonylamino and (C3-C7)cycloalkyl; and
n is 0, 1, 2, 3 or 4; or
(e) a selective COX-2 inhibitor of formula L, 
xe2x80x83a prodrug thereof or a pharmaceutically acceptable salt thereof or of said prodrug
xe2x80x83wherein the variables of the compound of formula L are defined as follows:
Ar is phenyl, (C3-C8)cycloalkyl, (C4-C8)cycloalkenyl or heteroaryl which is connected to Y through a carbon atom, the heteroaryl being selected from pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, furyl, thienyl, oxazolyl, thiazolyl, isooxazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxadiazolyl, triazolyl and tetrazolyl;
X1 is H, halo, (C1-C4)alkyl, hydroxy, (C1-C4)alkoxy, halo-substituted (C1-C4)alkyl, hydroxy-substituted (C1-C4)alkyl, (C1-C4)alkoxy(C1-C4)alkyl, amino, (C1-C4)alkylamino, di(C1-C4)alkylamino, amino (C1-C4)alkyl, (C1-C4)alkylamino(C1-C4)alkyl, di((C1-C4)alkylamino(C1-C4)alkyl, (C1-C4)alkanoylamino, di(C1-C4)alkanoylamino, (C1-C4)alkyl((C1-C4)alkanoyl)amino, (C1-C4)alkylsulfonylamino, (C1-C4)alkanoyl, carboxyl, (C1-C4)alkoxycarbonyl, aminocarbonyl, (C1-C4)alkylaminocarbonyl, di(C1-C4)alkylaminocarbonyl, cyano, nitro, mercapto, (C1-C4)alkylthio, (C1-C4)alkylsulfinyl, (C1-C4)alkylsulfonyl, aminosulfonyl, (C1-C4)alkylaminosulfonyl or di(C1-C4)alkylaminosulfonyl;
X2 and X3 are independently (C1-C4)alkyl, halo, halo-substituted (C1-C4)alkyl, hydroxy,
(C1-C4)alkoxy, mercapto, (C1-C4)alkylthio, (C1-C4)alkylsulfinyl, (C1-C4)alkylsulfonyl, (C1-C4)alkanoyl, carboxyl, (C1-C4)alkoxycarbonyl, aminocarbonyl, (C1-C4)alkylaminocarbonyl, di(C1-C4)alkylaminocarbonyl, cyano, nitro, amino, (C1-C4)alkylamino, di(C1-C4)alkylamino or (C1-C4)alkylsulfonylamino;
Y is xe2x80x94CR1xe2x95x90CR2-or xe2x80x94Cxe2x89xa1Cxe2x80x94, wherein R1 and R2 are independently H, methyl, ethyl or halo;
p is 0, 1, 2, 3, or 4; and
m and n are independently 0, 1, 2 or 3,
with the proviso that when Ar is phenyl; and p, m and n are O, Y is not xe2x80x94CHxe2x95x90CHxe2x80x94; and
when Ar is phenyl; p and m are 0; n is 1; and Y is xe2x80x94CHxe2x95x90CHxe2x80x94, X3 is not (C1-C4)alkoxy attached to the 2-position of Ar, nor amino, (C1-C4)alkylamino or di(C1-C4)alkylamino attached at the 4-position of Ar; or
(f) a selective COX-2 inhibitor of formula LX, 
xe2x80x83a prodrug thereof or a pharmaceutically acceptable salt thereof or of said prodrug
xe2x80x83wherein the variables of the compound of formula LX are defined as follows:
Xxe2x80x94Yxe2x80x94Zxe2x80x94 is selected from the group consisting of xe2x80x94C(O)xe2x80x94Oxe2x80x94CR5(R5)xe2x80x94 when side b is a double bond, and sides a and c are single bonds; and
R1 is selected from the group consisting of S(O)2CH3 and S(O)2NH2;
R2 is selected from the group consisting of (C1-C6)alkyl, (C3-C7)cycloalkyl, heteroaryl, benzoheteroaryl and mono- or di-substituted phenyl wherein the substituent is selected from the group consisting of hydrogen, halo, (C1-C6)alkoxy, (C1-C6)alkylthio, CN, CF3, (C1-C6)alkyl, N3, xe2x80x94CO2H, xe2x80x94CO2xe2x80x94(C1-C4)alkyl, xe2x80x94C(R5)(R6)xe2x80x94OH, xe2x80x94C(R5)(R6)xe2x80x94Oxe2x80x94(C1-C4)alkyl, and xe2x80x94(C1-C4)alkyl-CO2R
R5 and R6 are each independently selected from the group consisting of hydrogen and (C1-C6)alkyl,
or R5 and R6 together with the carbon to which they are attached from a saturated monocyclic carbon ring which is 3, 4, 5, 6 or 7 atoms.
This invention is especially directed to methods wherein the ARI, prodrug thereof or pharmaceutically acceptable salt of said ARI or said prodrug and the selective COX-2 inhibitor, prodrug thereof or pharmaceutically acceptable salt of said selective COX-2 inhibitor or said prodrug are administered separately in any order.
This invention is also especially directed to methods wherein the ARI, prodrug thereof or pharmaceutically acceptable salt of said ARI or said prodrug and the selective COX-2 inhibitor, prodrug thereof or pharmaceutically acceptable salt of said selective COX-2 inhibitor or said prodrug are administered together.
This invention is also directed to kits comprising:
a) a first unit dosage form comprising an aldose reductase inhibitor (ARI), a prodrug thereof or a pharmaceutically acceptable salt of said ARI or said prodrug and a pharmaceutically acceptable carrier, vehicle or diluent;
b) a second unit dosage form comprising
(a) a selective cyclooxygenase-2 (COX-2) inhibitor of formula I, 
xe2x80x83a prodrug thereof or a pharmaceutically acceptable salt thereof or of said prodrug,
xe2x80x83wherein the variables of the compound of formula I are defined as follows:
R1 is hydrogen or (C1-C4)alkyl; R2 is C(xe2x95x90Lxe2x80x2)R3 or SO2R4; Y is a direct bond or (C1-C4)alkylene; L and Lxe2x80x2 are independently oxygen or sulfur;
Q is selected from the following:
(Q-a) (C1-C6)alkyl;
(Q-b) halo-substituted (C1-C4)alkyl;
(Q-c) (C3-C7)cycloalkyl optionally substituted with one or two substituents independently selected from (C1-C4)alkyl, halo-substituted (C1-C4)alkyl, (C1-C4)alkoxy, hydroxy and halo;
(Q-d) phenyl or naphthyl, the phenyl and naphthyl being optionally substituted with one, two or three substituents independently selected from halo, (C1-C4)alkyl, halo-substituted (C1-C4)alkyl, hydroxy, (C1-C4)alkoxy, nitro, halo-substituted (C1-C4)alkoxy, S(O)mR5, SO2NH2, SO2N((C1C4)alkyl)2, amino, (C1-C4)alkylamino, di-((C1-C4)alkyl)amino, NR1C(O)R5, CN, (C1-C4)alkyl-OH and (C1-C4)alkyl-OR5;
(Q-e) a 5-membered monocyclic aromatic group containing one heteroatom selected from O, S and N and optionally containing one, two or three nitrogen atom(s) in addition to said heteroatom, and said monocyclic aromatic group being optionally substituted with one, two or three substituents independently selected from halo, (C1-C4)alkyl, halo-substituted (C1-C4)alkyl, hydroxy, (C1-C4)alkoxy, halo-substituted (C1-C4)alkoxy, amino, (C1-C4)alkylamino, di-((C1-C4)alkyl)amino, (C1--C4)alkyl-OH and (C1-C4)alkyl-OR5; and
(Q-f) a 6-membered monocyclic aromatic group containing one nitrogen atom and optionally containing one, two or three additional nitrogen atom(s), and said monocyclic aromatic group being optionally substituted with one, two or three substituents independently selected from halo, (C1-C4)alkyl, halo-substituted (C1-C4)alkyl, hydroxy, (C1-C4)alkoxy, halo-substituted (C1-C4)alkoxy, amino, (C1-C4)alkylamino, di-((C1-C4)alkyl)amino, (C1-C4)alkyl-OH and (C1-C4)alkyl-OR5;
R3 is xe2x80x94OR6, xe2x80x94NR7R8, N(OR1)R7 or a group of formula: 
xe2x80x83Z is a direct bond, oxygen, sulfur or NR5;
R4 is (C1-C6)alkyl, halo-substituted (C1-C4)alkyl, (C1-C4)alkyl-OH, xe2x80x94NR7R8, phenyl or naphthyl, the phenyl and naphthyl being optionally substituted with one, two or three substituents independently selected from halo, (C1-C4)alkyl, halo-substitutued (C1-C4)alkyl hydroxy, (C1-C4)alkoxy and halo-substitutued (C1-C4)alkoxy;
R5 is (C1-C4)alkyl or halo-substituted (C1-C4)alkyl;
R6 is (C1-C4)alkyl, (C3-C7)cycloalkyl, (C1-C4)alkyl-(C3-C7)cycloalkyl, halo-substitutued (C1-C4)alkyl, (C1-C4)alkyl-phenyl or phenyl, the phenyl moiety being optionally substituted with one, or two substituents independently selected from halo, (C1-C4)alkyl, halo-substitutued (C1-C4)alkyl, hydroxy, (C1-C4)alkoxy, (C1-C4)alkylthio, amino, di-((C1-C4)alkyl)amino and nitro;
R7 and R8 are independently selected from I hydrogen, (ii) (C1-C6)alkyl optionally substituted with a substituent independently selected from halo, hydroxy, (C1-C4)alkoxy, amino, (C1-C4)alkylamino and di-((C1-C4)alkyl)amino, (iii) (C3-C7)cycloalkyl optionally substituted with a substituent independently selected from hydroxy, (C1-C4)alkyl and (C1-C4)alkoxy, (iv) (C1-C4)alkyl-(C3-C7)cycloalkyl optionally substituted with a substituent independently selected from hydroxy, (C1-C4)alkyl and (C1-C4)alkoxy, and (v) (C1-C4)alkyl-phenyl or phenyl, the phenyl moiety being optionally substituted with one or two substituents independently selected from halo, (C1-C4)alkyl, halo-substitutued (C1-C4)alkyl, hydroxy, (C1-C4)alkoxy, (C1-C4)alkylthio, nitro, amino, di-((C1-C4)alkyl)amino and CN;
X is independently selected from halo, (C1-C4)alkyl, halo-substitutued (C1-C4)alkyl, hydroxy, (C1-C4)alkoxy, halo-substitutued (C1-C4)alkoxy, (C1-C4)alkylthio, nitro, amino, di-((C1-C4)alkyl)amino and CN;
m is 0, 1 or 2; n is 0, 1, 2 or 3; and r is 1, 2 or 3; or
(b) a selective COX-2 inhibitor of formula XX, 
xe2x80x83a prodrug thereof or a pharmaceutically acceptable salt thereof or of said prodrug,
xe2x80x83wherein the variables of the compound of formula XX are defined as follows:
A is a partially unsaturated or unsaturated five membered heterocyclic, or a partially unsaturated or unsaturated five membered carbocyclic, wherein the 4-(sulfonyl)phenyl and the 4-substituted phenyl in the formula XX are attached to ring atoms of Ring A adjacent to each other;
R1 is aryl or heteroaryl, and the aryl or heteroaryl being optionally substituted by one to four substituents selected from halo, (C1-C4)alkyl, halo-substituted (C1-C4)alkyl, (C1-C4)alkoxy, (C1-C4)alkyl carbonyl, hydroxy, nitro, cyano and amino, with the proviso that when A is pyrazole, R1 is heteroaryl;
R2 is (C1-C4)alkyl, halo-substituted (C1-C4)alkyl, (C1-C4)alkylamino, (C1-C4)dialkylamino or amino;
R3, R4 and R5 are independently hydrogen, halo, (C1-C4)alkyl, halo-substituted (C1-C4)alkyl, (C2-C5)alkenyl, (C2-C5)alkynyl, (C1-C4)alkoxy, hydroxy-(C1-C4)alkyl, (C1-C4)alkoxy (C1-C4)alkyl, (C1-C4)alkanoyl, cyano, nitro, cyano (C1-C4)alkyl, carboxy, (C1-C4)alkoxycarbonyl, aminocarbonyl, Nxe2x80x94(C1-C4)alkylaminocarbonyl, N,Nxe2x80x94di-(C1-C4)alkylaminocarbonyl, N-arylaminocarbonyl, N,N-diarylaminocarbonyl, Nxe2x80x94(C1-C4)alkyl-N-arylaminocarbonyl, aryl, aryloxy, aryloxy-(C1-C4)alkyl, heteroaryl, heteroaryloxy, heteroaryloxy-(C1-C4)alkyl, morpholino-carbonyl, C1-C4)alkoxyaminocarbonyl or (C1-C4)alkyl-carbonylamino; or two of R3, R4 and R5 are taken together with atoms to which they are attached and form a 4-7 membered ring;
R6 and R7 are independently hydrogen, halo, (C1-C4)alkyl, halo-substituted (C1-C4)alkyl, (C1-C4)alkoxy, (C1-C4)alkylthio, (C1-C4)alkylamino, N,N-di (C1-C4)alkylamino, hydroxyl-(C1-C4)alkyl, (C1-C4)alkoxy-(C1-C4)alkyl, (C1-C4)alkyl-(C1-C4)alkoxy, C1-C4)alkylamino-(C1-C4)alkyl, hydroxy, amino-(C1-C4)alkyl and N,N-di (C1-C4)alkylamino-(C1C4)alkyl; and
m and n are independently 1, 2, 3 or 4,
with the proviso that when A contains an oxygen or sulfur heteroatom, one of R3, R4 or R5 is absent; or
(c) a selective COX-2 inhibitor of formula XXX, 
xe2x80x83a prodrug thereof or a pharmaceutically acceptable salt thereof or of said prodrug,
xe2x80x83wherein variables of the compound of formula XXX are defined as follows:
Ar is heteroaryl selected from a 5-membered monocyclic aromatic ring having one hetero atom selected from O, S and N and optionally containing one to three N atom(s) in addition to said hetero atom, or a 6-membered monocyclic aromatic ring having one N atom and optionally containing one to four N atom(s) in addition to said N atom; and said heteroaryl being connected to the nitrogen atom on the benzimidazole through a carbon atom on the heteroaryl ring;
X1 is independently selected from halo, (C1-C4)alkyl, hydroxy, (C1-C4)alkoxy, halo-substituted (C1-C4)alkyl, hydroxy-substituted (C1-C4)alkyl, ((C1-C4)alkoxy) (C1-C4)alkyl, halo-substituted (C1-C4)alkoxy, amino, Nxe2x80x94((C1-C4)alkyl)amino, N, N-di((C1-C4)alkyl)amino, [Nxe2x80x94((C1-C4)alkyl)amino](C1-C4)alkyl, [N,N-di((C1-C4)alkyl)amino](C1-C4)alkyl, Nxe2x80x94((C1-C4)alkanoyl)amino, Nxe2x80x94((C1-C4)alkyl)-Nxe2x80x94((C1-C4)alkanoyl)amino, Nxe2x80x94[((C1-C4)alkyl)sulfonyl]amino, N-[(halo-substituted (C1-C4)alkyl)sulfonyl]amino, (C1-C4)alkanoyl, carboxy, ((C1-C4)alkoxy)carbonyl, carbamoyl, [Nxe2x80x94((C1-C4)alkyl)amino]carbonyl, [N,N-di((C1-C4)alkyl)amino]carbonyl, cyano, nitro, mercapto, ((C1-C4)alkyl)thio, ((C1-C4)alkyl)sulfinyl, ((C1-C4)alkyl)sulfonyl, aminosulfonyl, [Nxe2x80x94((C1C4)alkyl)amino]sulfonyl and [N,N-di((C1-C4)alkyl)amino]sulfonyl;
X2 is independently selected from halo, (C1-C4)alkyl, hydroxy, (C1-C4)alkoxy, halo-substituted (C1-C4)alkyl, hydroxy-substituted (C1-C4)alkyl, ((C1-C4)alkoxy)(C1-C4)alkyl, halo-substituted (C1-C4)alkoxy, amino, Nxe2x80x94((C1-C4)alkyl)amino, N,N-di((C1-C4)alkyl)amino, [Nxe2x80x94((C1-C4)alkyl)amino](C1-C4)alkyl, [N,N-di((C1-C4)alkyl)amino](C1-C4)alkyl, Nxe2x80x94((C1-C4)alkanoyl)amino, Nxe2x80x94((C1-C4)alkyl)-Nxe2x80x94((C1-C4)alkanoyl)amino, Nxe2x80x94[((C1-C4)alkyl)sulfonyl]amino, N-[(halo-substituted (C1-C4)alkyl)sulfonyl]amino, (C1-C4)alkanoyl, carboxy, ((C1-C4)alkoxy)carbonyl, carbamoyl, [Nxe2x80x94((C1-C4)alkyl)amino]carbonyl, [N,N-di((C1-C4)alkyl)amino]carbonyl, N-carbamoylamino, cyano, nitro, mercapto, ((C1-C4)alkyl)thio, ((C1-C4)alkyl)sulfinyl, ((C1-C4)alkyl)sulfonyl, aminosulfonyl, [Nxe2x80x94((C1-C4)alkyl)amino]sulfonyl and [N,N-di((C1-C4)alkyl)amino]sulfonyl;
R1 is selected from
hydrogen;
straight or branched (C1-C4)alkyl optionally substituted with up to three substituents wherein said substituents are independently selected from halo, hydroxy, (C1-C4)alkoxy, amino, Nxe2x80x94((C1-C4)alkyl)amino and N,N-di((C1-C4)alkyl)amino;
(C3-C8)cycloalkyl optionally substituted with up to three substituents wherein said substituents are independently selected from halo, (C1-C4)alkyl, hydroxy, (C1-C4)alkoxy, amino, Nxe2x80x94((C1-C4)alkyl)amino and N,N-di((C1-C4)alkyl)amino;
(C4-C8) cycloalkenyl optionally substituted with up to three substituents wherein said substituents are independently selected from halo, (C1-C4)alkyl, hydroxy, (C1-C4)alkoxy, amino, Nxe2x80x94((C1-C4)alkyl)amino and N,N-di((C1-C4)alkyl)amino;
phenyl optionally substituted with up to three substituents wherein said substituents are independently selected from halo, (C1-C4)alkyl, hydroxy, (C1-C4) alkoxy, halo-substituted (C1-C4)alkyl, hydroxy-substituted (C1-C4)alkyl, ((C1-C4)alkoxy)(C1-C4)alkyl, halo-substituted (C1-C4)alkoxy, amino, Nxe2x80x94((C1-C4)alkyl)amino, N,N-di((C1-C4)alkyl)amino, [Nxe2x80x94((C1-C4)alkyl)amino](C1-C4)alkyl, [N, N-di((C1-C4)alkyl)amino](C1-C4)alkyl, Nxe2x80x94((C1-C4)alkanoyl)amino, Nxe2x80x94[((C1-C4)alkyl) ((C1-C4)alkanoyl)]amino, Nxe2x80x94[((C1-C4)alkyl)sulfonyl]amino, N-[(halo-substituted (C1-C4)alkyl)sulfonyl]amino, (C1-C4)alkanoyl, carboxy, ((C1-C4)alkoxy)carbonyl, carbamoyl, [Nxe2x80x94((C1-C4)alkyl)amino]carbonyl, [N,N-di((C1-C4)alkyl)amino]carbonyl, cyano, nitro, mercapto, ((C1-C4)alkyl)thio, ((C1-C4)alkyl)sulfinyl, ((C1-C4)alkyl)sulfonyl, aminosulfonyl, [Nxe2x80x94((C1-C4)alkyl)amino]sulfonyl and [N,N-di((C1-C4)alkyl)amino]sulfonyl; and
heteroaryl selected from
a 5-membered monocyclic aromatic ring having one hetero atom selected from O, S and N and optionally containing one to three N atom(s) in addition to said hetero atom; or
a 6-membered monocyclic aromatic ring having one N atom and optionally containing one to four N atom(s) in addition to said N atom; and
said heteroaryl is optionally substituted with up to three substituents selected from X1;
R2 and R3 are independently selected from
hydrogen;
halo;
(C1-C4)alkyl;
phenyl optionally substituted with up to three substituents wherein said substituents are independently selected from halo, (C1-C4)alkyl, hydroxy, (C1-C4)alkoxy, amino, Nxe2x80x94((C1-C4)alkyl)amino and N,N-di((C1-C4)alkyl)amino;
m is 0, 1, 2, 3, 4 or 5; and
n is 0, 1, 2, 3 or 4; or
(d) a a selective COX-2 inhibitor of formula XL, 
xe2x80x83a prodrug thereof or a pharmaceutically acceptable salt thereof or of said prodrug
xe2x80x83wherein the variables of the compound of formula XL are defined as follows:
Z is OH, (C1-C6)alkoxy, xe2x80x94NR2R3 or a group of formula II or formula III: 
xe2x80x83wherein r is 1, 2, 3 or 4, Y is a direct bond, O, S or NR4, and W is OH or xe2x80x94NR2R3;
Q is selected from the following:
(A) phenyl optionally substituted with one, two or three substituents independently selected from
I halo, (C1-C4)alkyl, halo-substituted (C1-C4)alkyl, OH, (C1-C4)alkoxy, halo-substituted (C1-C4)alkoxy, (C1-C4)alkylthio, NO2, NH2, di-((C1-C4)alkyl)amino, (C1-C4)alkylamino, CN, HOxe2x80x94(C1-C4)alkyl, (C1-C4)alkoxy-(C1-C4)alkyl, (C1-C4)alkylsulfonyl, aminosulfonyl, xe2x80x94NH2S(O)2NR2R3, acetyl, xe2x80x94COOH, xe2x80x94C(O)Oxe2x80x94(C1-C4)alkyl, (C1-C4)alkylsulfonylamino and (C3-C7)cycloalkyl;
(ii) aryl or xe2x80x94Oxe2x80x94(CH2)n-aryl, wherein either aryl moiety is optionally substituted with one, two or three substituents independently selected from halo, (C1-C4)alkyl, halo-substituted (C1-C4)alkyl, OH, (C1-C4)alkoxy, halo-substituted (C1-C4)alkoxy, (C0-C4)alkylthio, NO2, NH2, di-((C1-C4)alkyl)amino, (C1-C4)alkylamino and CN;
(iii) 5-membered monocyclic aromatic group optionally substituted with one, two or three substituents independently selected from halo, (C1-C4)alkyl, halo-substituted (C1-C4)alkyl, OH, (C1-C4)alkoxy, halo-substituted (C1-C4)alkoxy, (C1-C4)alkylthio, NO2, NH2, di-((C1-C4)alkyl)amino, (C1-C4)alkylamino and CN;
(iv) 6-membered monocyclic aromatic group optionally substituted with one, two or three substituents independently selected from halo, (C1-C4)alkyl, halo-substituted (C1-C4)alkyl, OH, (C1-C4)alkoxy, halo-substituted (C1-C4)alkoxy, (C1-C4)alkylthio, NO2, NH2, di-((C1-C4)alkyl)amino, (C1-C4)alkylamino and CN;
(B) a 6-membered monocyclic aromatic group containing one, two, three or four nitrogen atom(s), and said monocyclic aromatic group being optionally substituted with one, two or three substituents independently selected from the above group i, ii, iii and iv;
(C) a 5-membered monocyclic aromatic group containing one heteroatom selected from O, S and N and optionally containing one, two or three nitrogen atom(s) in addition to said heteroatom, and said monocyclic aromatic group being optionally substituted with one, two or three substituents independently selected from the above group i, ii, iii and iv;
(D) (C3-C7)cycloalkyl optionally substituted with one or two substituents independently selected from OH, (C1-C4)alkyl, halo and halo-substituted (C1-C4)alkyl; and
(E) a benzo-fused heterocycle optionally substituted with one, two or three substituents independently selected from the group (a-1);
R1 is hydrogen, (C1-C4)alkyl or halo;
R2 and R3 are independently H, OH, (C1-C4)alkoxy, (C1-C4)alkyl or (C1-C4)alkyl substituted with halo, OH, (C1-C4)alkoxy, NH2 or CN;
R4 is hydrogen or (C1-C4)alkyl;
X is independently selected from halo, (C1-C4)alkyl, halo-substituted (C1-C4)alkyl, OH, (C1-C4)alkoxy, halo-substituted (C1-C4)alkoxy, (C1-C4)alkylthio, NO2, NH2, di-((C1-C4)alkyl)amino, (C1-C4)alkylamino, CN, HOxe2x80x94(C1-C4)alkyl, (C1-C4) alkoxy-(C1-C4)alkyl, (C1-C4)alkylsulfonyl, aminosulfonyl, xe2x80x94NH2S(O)2N R2NR3, acetyl, xe2x80x94COOH, xe2x80x94C(O)Oxe2x80x94(C1-C4)alkyl, (C1-C4)alkylsulfonylamino and (C3-C7)cycloalkyl; and
n is 0, 1, 2, 3 or 4; or
(e) a selective COX-2 inhibitor of formula L, 
xe2x80x83a prodrug thereof or a pharmaceutically acceptable salt thereof or of said prodrug
xe2x80x83wherein the variables of the compound of formula L are defined as follows:
Ar is phenyl, (C3-C8)cycloalkyl, (C4-C8)cycloalkenyl or heteroaryl which is connected to Y through a carbon atom, the heteroaryl being selected from pyridyl, pyridazinyl, pyrimidinyl, pyrazinyl, pyrrolyl, furyl, thienyl, oxazolyl, thiazolyl, isooxazolyl, isothiazolyl, imidazolyl, pyrazolyl, oxadiazolyl, triazolyl and tetrazolyl;
X1 is H, halo, (C1-C4)alkyl, hydroxy, (C1-C4)alkoxy, halo-substituted (C1-C4)alkyl, hydroxy-substituted (C1-C4)alkyl, (C1-C4)alkoxy(C1-C4)alkyl, amino, (C1-C4)alkylamino, di(C1-C4)alkylamino, amino (C1-C4)alkyl, (C1-C4)alkylamino(C1-C4)alkyl, di(C1-C4)alkylamino(C1-C4)alkyl, (C1-C4)alkanoylamino, di(C1-C4)alkanoylamino, (C1-C4)alkyl((C1-C4)alkanoyl)amino, (C1-C4)alkylsulfonylamino, (C1-C4)alkanoyl, carboxyl, (C1-C4)alkoxycarbonyl, aminocarbonyl, (C1-C4)alkylaminocarbonyl, di(C1-C4)alkylaminocarbonyl, cyano, nitro, mercapto, (C1-C4)alkylthio, (C1-C4)alkylsulfinyl, (C1-C4)alkylsulfonyl, aminosulfonyl, (C1-C4)alkylaminosulfonyl or di(C1-C4)alkylaminosulfonyl;
X2 and X3 are independently (C1-C4)alkyl, halo, halo-substituted (C1-C4)alkyl, hydroxy, (C1-C4)alkoxy, mercapto, (C1-C4)alkylthio, (C1-C4)alkylsulfinyl, (C1-C4)alkylsulfonyl, (C1-C4)alkanoyl, carboxyl, (C1-C4)alkoxycarbonyl, aminocarbonyl, (C1-C4)alkylaminocarbonyl, di(C1-C4)alkylaminocarbonyl, cyano, nitro, amino, (C1-C4)alkylamino, di(C1-C4)alkylamino or (C1-C4)alkylsulfonylamino;
Y is xe2x80x94CR1xe2x95x90CR2xe2x80x94 or xe2x80x94Cxe2x89xa1Cxe2x80x94, wherein R1 and R2 are independently H, methyl, ethyl or halo;
p is 0, 1, 2, 3 or 4; and
m and n are independently 0, 1, 2 or 3,
with the proviso that when Ar is phenyl; and p, m and n are O, Y is not xe2x80x94CHxe2x95x90CHxe2x80x94; and
when Ar is phenyl; p and m are 0; n is 1; and Y is xe2x80x94CHxe2x95x90CHxe2x80x94, X3 is not (C1-C4)alkoxy attached to the 2-position of Ar, nor amino, (C1-C4)alkylamino or di(C1-C4)alkylamino attached at the 4-position of Ar; or
(f) a selective COX-2 inhibitor of formula LX, 
xe2x80x83a prodrug thereof or a pharmaceutically acceptable salt thereof or of said prodrug
xe2x80x83wherein the variables of the compound of formula LX are defined as follows:
Xxe2x80x94Yxe2x80x94Zxe2x80x94 is selected from the group consisting of xe2x80x94C(O)xe2x80x94Oxe2x80x94CR5(R5)xe2x80x94 when side b is a double bond, and sides a and c are single bonds; and
R1 is selected from the group consisting of S(O)2CH3 and S(O)2NH2;
R2 is selected from the group consisting of (C1-C6)alkyl, (C3-C7)cycloalkyl, heteroaryl, benzoheteroaryl and mono- or di-substituted phenyl wherein the substituent is selected from the group consisting of hydrogen, halo, (C1-C6)alkoxy, (C1-C6)alkylthio, CN, CF3, (C1-C6)alkyl, N3, xe2x80x94CO2H, xe2x80x94CO2xe2x80x94(C1-C4)alkyl, xe2x80x94C(R5)(R)xe2x80x94OH, xe2x80x94C(R5)(R6)xe2x80x94Oxe2x80x94(C1-C4)alkyl, and xe2x80x94(C1-C6)alkyl-CO2R5;
R5 and R6 are each independently selected from the group consisting of hydrogen and (C1-C6)alkyl,
or R5 and R6 together with the carbon to which they are attached from a saturated monocyclic carbon ring which is 3, 4, 5, 6 or 7 atoms and a pharmaceutically acceptable carrier, vehicle or diluent; and
c) a container.
In the compositions, methods and kits of this invention, it is preferred that said ARI is fidarestat, epalrestat, minalrestat, SPR-210, zenarastat or zopolrestat, a prodrug thereof or a pharmaceutically acceptable salt of said ARI or of said prodrug. It is especially preferred that said ARI is zopolrestat, a prodrug thereof or a pharmaceutically acceptable salt of zopolrestat or of said prodrug and that said selective COX-2 inhibitor is rofecoxib, a prodrug thereof or a pharmaceutically acceptable salt of rofecoxib or of said prodrug.